Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase

ABSTRACT

Heterocyclic amides of formula (1)  
                 
wherein: X is N or CH; 
     R 4  and R 5  together are either —S—C(R 6 )═C(R 7 )— or —C(R 7 )═C(R 6 )—S—;    R 6  and R 7  are independently selected from, for example hydrogen, halo and C l-4 alkyl; A is phenylene or heteroarylene; n is 0, 1 or 2;    R 1  is selected from for example halo, nitro, cyano, hydroxy, carboxy;    R 2  is hydrogen, hydroxy or carboxy;    R 3  is selected from for example hydrogen, hydroxy, aryl, heterocyclyl and C 1-4 alkyl(optionally substituted by 1 or 2 R 8  groups);    R 8  is selected from for example hydroxy, —COCOOR 9 , —C(O)N(R 9 )(R 10 ), —NHC(O)R 9 , (R 9 )(R 10 )N— and —COOR 9 ;    R 9  and R 10  are selected from for example hydrogen, hydroxy, C 1-4 alkyl (optionally substituted by 1 or 2 R 13 );    R 13  is selected from hydroxy, halo, trihalomethyl and C 1-4 alkoxy; or a pharmaceutically acceptable salt or pro-drug thereof; possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity. Processes for the manufacture of said heterocyclic amide derivatives and pharmaceutical compositions containing them are described.

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB03/00877, filed Mar. 4, 2003, whichclaims priority from United Kingdom Patent Application No. 0205165.4,filed Mar. 6, 2002, the specification of which is incorporated byreference herein. International Application No. PCT/GB03/00877 waspublished under PCT Article 21(2) in English.

The present invention relates to heterocyclic amide derivatives,pharmaceutically acceptable salts and in vivo hydrolysable estersthereof. These heterocyclic amides possess glycogen phosphorylaseinhibitory activity and accordingly have value in the treatment ofdisease states associated with increased glycogen phosphorylase activityand thus are potentially useful in methods of treatment of awarm-blooded animal such as man. The invention also relates to processesfor the manufacture of said heterocyclic amide derivatives, topharmaceutical compositions containing them and to their use in themanufacture of medicaments to inhibit glycogen phosphorylase activity ina warm-blooded animal such as man.

The liver is the major organ regulating glycaemia in the post-absorptivestate. Additionally, although having a smaller role in the contributionto post-prandial blood glucose levels, the response of the liver toexogenous sources of plasma glucose is key to an ability to maintaineuglycaemia. An increased hepatic glucose output (HGO) is considered toplay an important role in maintaining the elevated fasting plasmaglucose (FPG) levels seen in type 2 diabetics; particularly those with aFPG >140 mg/dl (7.8 mM). (Weyer et al, (1999), J Clin Invest 104:787-794; Clore & Blackgard (1994), Diabetes 43: 256-262; De Fronzo, R.A., et al, (1992) Diabetes Care 15; 318-355; Reaven, G. M. (1995)Diabetologia 38; 3-13).

Since current oral, anti-diabetic therapies fail to bring FPG levels towithin the normal, non-diabetic range and since raised FPG (andglycHbAlc) levels are risk factors for both macro—(Charles, M. A. et al(1996) Lancet 348, 1657-1658; Coutinho, M. et al (1999) Diabetes Care22; 233-240; Shaw, J. E. et al (2000) Diabetes Care 23, 34-39) andmicro-vascular disease (DCCT Research Group (1993) New. Eng. J. Med.329; 977-986); the reduction and normalisation of elevated FPG levelsremains a treatment goal in type 2 DM.

It has been estimated that, after an overnight fast, 74% of HGO wasderived from glycogenolysis with the remainder derived fromgluconeogenic precursors (Hellerstein et al (1997) Am J Physiol, 272:E163). Glycogen phosphorylase is a key enzyme in the generation byglycogenolysis of glucose-1-phosphate, and hence glucose in liver andalso in other tissues such as muscle and neuronal tissue.

Liver glycogen phosphorylase a activity is elevated in diabetic animalmodels including the db/db mouse and the fa/fa rat (Aiston S et al(2000). Diabetalogia 43, 589-597).

Inhibition of hepatic glycogen phosphorylase with chloroindoleinhibitors (CP91149 and CP320626) has been shown to reduce both glucagonstimulated glycogenolysis and glucose output in hepatocytes (Hoover etal (1998) J Med Chem 41, 2934-8; Martin et al (1998) PNAS 95, 1776-81).Additionally, plasma glucose concentration is reduced, in a dose relatedmanner, db/db and ob/ob mice following treatment with these compounds.

Studies in conscious dogs with glucagon challenge in the absence andpresence of another glycogen phosphorylase inhibitor, Bay K 3401, alsoshow the potential utility of such agents where there is elevatedcirculating levels of glucagon, as in both Type 1 and Type 2 diabetes.In the presence of Bay R 3401, hepatic glucose output and arterialplasma glucose following a glucagon challenge were reduced significantly(Shiota et al, (1997), Am J Physiol, 273: E868).

The heterocyclic amides of the present invention possess glycogenphosphorylase inhibitory activity and accordingly are expected to be ofuse in the treatment of type 2 diabetes, insulin resistance, syndrome X,hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia and obesity,particularly type 2 diabetes.

According to one aspect of the present invention there is provided acompound of formula (1):

wherein:

is a single or double bond;

-   X is N or CH;-   R⁴ and R⁵ together are either —S—C(R⁶)═C(R⁷)— or —C(R⁷)═C(R⁶)—S—;-   R⁶ and R⁷ are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl,    trifluoromethoxy, carboxy, carbamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,    C₂₋₄alkynyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;-   A is phenylene or heteroarylene;-   n is 0, 1 or 2;-   R¹ is independently selected from halo, nitro, cyano, hydroxy,    carboxy, carbamoyl, N—C₁₋₄alkylcarbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl,    sulphamoyl, N—C₁₋₄alkylsulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl,    —S(O)_(b)C₁₋₄alkyl (wherein b is 0, 1, or 2), C₁₋₄alkyl,    C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,    hydroxyC₁₋₄alkyl, fluoromethyl, difluoromethyl, trifluoromethyl and    trifluoromethoxy;-   or, when n is 2, the two R¹ groups, together with the carbon atoms    of A to which they are attached, may form a 4 to 7 membered ring,    optionally containing 1 or 2 heteroatoms independently selected from    O, S and N, and optionally being substituted by one or two methyl    groups;-   R² is hydrogen, hydroxy or carboxy;-   R³ is selected from hydrogen, hydroxy, C₁₋₄alkoxy, C₁₋₄alkanoyl,    carbamoyl,-   C₃₋₇cycloalkyl (optionally substituted with 1 or 2 hydroxy groups),    cyano(C₁₋₄)alkyl, aryl, heterocyclyl, C₁₋₄alkyl (optionally    substituted by 1 or 2 R⁸ groups), and groups of the formulae B and    B′:    wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided    that the hydroxy group is not a substituent on the ring carbon    adjacent to the ring oxygen;    -   R⁸ is independently selected from hydroxy, C₁₋₄alkoxyC₁₋₄alkoxy,        hydroxyC₁₋₄alkoxy, 5- and 6-membered cyclic acetals and mono-        and di-methyl derivatives thereof, aryl, heterocyclyl,        C₃₋₇cycloalkyl, C₁₋₄alkanoyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b)—        (wherein b is 0, 1 or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is        0, 1 or 2), arylS(O)_(b)— (wherein b is 0, 1 or 2),        heterocyclylS(O)_(b)— (wherein b is 0, 1 or 2), benzylS(O)_(b)—        (wherein b is 0, 1 or 2), —N(OH)CHO, —C(═N—OH)NH₂,        —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂,        —C(═N—OH)NHC₃₋₆cycloalkyl, —C(═N—OH)N(C₃₋₆cycloalkyl)₂,        —COCOOR⁹, —C(O)N(R⁹)(R¹⁰), —NHC(O)R⁹, —C(O)NHSO₂(C₁₋₄alkyl),        —NHSO₂R⁹, (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹, (R⁹)(R¹⁰)N— and —COOR⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl (optionally substituted by 1 or 2 R¹³), C₃₋₇cycloalkyl        (optionally substituted by 1 or 2 hydroxy groups),        cyano(C₁₋₄)alkyl, trihalo(C₁₋₄)alkyl, aryl, heterocyclyl and        heterocyclyl(C₁₋₄alkyl); or    -   R⁹ and R¹⁰ together with the nitrogen to which they are attached        form a 4- to 6-membered ring where the ring is optionally        substituted on carbon by 1 or 2 substituents independently        selected from oxo, hydroxy, carboxy, halo, nitro, cyano,        carbonyl,-   C₁₋₄alkoxy and heterocyclyl; or the ring may be optionally    substituted on two adjacent carbons by —O—CH₂—O— to form a cyclic    acetal wherein one or both of the hydrogens of the —O—CH₂—O— group    may be replaced by a methyl;    -   R¹³ is selected from hydroxy, halo, trihalomethyl and        C₁₋₄alkoxy;    -   R¹¹ is independently selected from hydrogen, C₁₋₄alkyl and        hydroxyC₁₋₄alkyl;-   or a pharmaceutically acceptable salt or pro-drug thereof;-   with the proviso that the compound of formula (1) is not:-   i)    2,3-dichloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole;-   ii)    2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;    or-   iii)    2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

In another aspect is provided a compound of the formula (1): wherein:

is a single or double bond;

-   X is N or CH;-   R⁴ and R⁵ together are either —S—C(R⁶)═C(R⁷)— or —C(R⁷)═C(R⁶)—S—;-   wherein R⁶ and R⁷ are independently selected from hydrogen, halo,    nitro, cyano, hydroxy, fluoromethyl, difluoromethyl,    trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,    mercapto, sulfamoyl, ureido, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,    N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,    N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,    C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,    C₁₋₆alkylsulphonylamino and C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino;    wherein:-   A is phenylene or heteroarylene;-   n is 0, 1 or 2;-   wherein R¹ is independently selected from hydrogen, halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, N—C₁₋₄alkylcarbamoyl,    N,N—(C₁₋₄alkyl)₂carbamoyl, sulphamoyl, N—C₁₋₄alkylsulphamoyl,    N,N—(C₁₋₄alkyl)₂sulphamoyl, sulfino, sulfo, C₁₋₄alkyl, C₂₋₄alkenyl,    C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,    N—(C₁₋₄alkyl)amino,-   N,N—(C₁₋₄alkyl)₂amino, hydroxyC₁₋₄alkyl, fluoromethyl,    difluoromethyl, trifluoromethyl, trifluoromethoxy, C₁₋₄alkoxy and-   R¹ is of the formula A′ or A″:     —CH₂CH(OH)(CH₂)_(u)CO₂H  (A″)-   wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided    that the hydroxy group is not a substituent on the ring carbon    adjacent to the ring oxygen;-   R² is hydrogen, hydroxy or carboxy;-   R³ is selected from hydrogen, hydroxy, C₁₋₄alkanoyl, carbamoyl,    C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups provided    that when there are 2 hydroxy groups they are not substituents on    the same carbon), C₅₋₇cycloalkyl (optionally substituted with 1 or 2    hydroxy groups provided that when there are 2 hydroxy groups they    are not substituents on the same carbon), cyano(C₁₋₄)alkyl,    4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl,    1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl,    C₁₋₄alkyl [substituted by 1 or 2 R⁸ groups (provided that when there    are 2 R⁸ groups they are not substituents on the same carbon)] and    groups of the formulae B and B′:-   wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided    that the hydroxy group is not a substituent on the ring carbon    adjacent to the ring oxygen);    -   {wherein R⁸ is independently selected from hydroxy,        C₁₋₄alkoxyC₁₋₄alkoxy, hydroxyC₁₋₄alkoxy,        2,2-dimethyl-1,3-dioxolan-4-yl, heterocyclyl, C₁₋₄alkanoyl,    -   C₁₋₄alkoxy, C₁₋₄alkanesulfinyl, C₁₋₄alkanesulfonyl, —N(OH)CHO,        —COCOOR⁹, (R⁹)(R¹⁰)NCO—, (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹, (R⁹)(R¹⁰)N—        and —COOR⁹;    -   [wherein R⁹ and R¹⁰ are independently selected from hydrogen,        hydroxy, C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy        groups provided that when there are 2 hydroxy groups they are        not substituents on the same carbon), C₅₋₇cycloalkyl (optionally        substituted by 1 or 2 hydroxy groups provided that when there        are 2 hydroxy groups they are not substituents on the same        carbon), cyano(C₁₋₄)alkyl, 4-butanolidyl, 5-pentanolidyl,        tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl,        1,1-dioxotetrahydrothiopyranyl, 2,2-dimethyl-1,3-dioxolan-4-yl        and C₁₋₄alkyl substituted by R¹³;    -   (wherein R¹³ is selected from hydroxy, C₁₋₄alkoxy, heterocyclyl,        C₁₋₄alkanoyl, C₁₋₄alkanesulfinyl, C₁₋₄alkanesulfonyl, —N(OH)CHO,        (R¹¹)(R¹²)NCO—, (R¹¹)(R¹²)NSO₂—, —COCH₂OR¹¹, (R¹¹)(R¹²)N—    -   {wherein R¹¹ and R¹² are independently selected from hydrogen,        C₁₋₄alkyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, C₁₋₄alkylS(O)_(b)        (wherein b is 0, 1 or 2)}); and    -   R⁹ and R¹⁰ can together with the nitrogen to which they are        attached form 4- to 6-membered ring where the ring is optionally        substituted on carbon by 1 or 2 substituents selected from oxo,        hydroxy, carboxy, halo, nitro, nitroso, cyano, isocyano, amino,        N—C₁₋₄alkylamino, N,N—(C₁₋₄)₂alkylamino, carbonyl, sulfo,        C₁₋₄alkoxy, heterocyclyl, C₁₋₄alkanoyl, C₁₋₄alkanesulfinyl,        C₁₋₄alkanesulfonyl, —N(OH)CHO, (R¹¹)(R¹²)NCO—, (R¹¹)(R¹²)NSO₂—,        —COCH₂OR¹¹, (R¹¹)(R¹²)N—;-   wherein R¹¹ and R¹² are as defined above]};-   provided that when R¹ is of the formula A′ or A″ then R³ does not    contain a group of the formula B or B′ and when R³ is of the formula    B or B′ then R¹ does not contain a group of the formula A′ or A″;-   or a pharmaceutically acceptable salt or in vivo hydrolysable ester    thereof; with the proviso that the compound of formula (1) is not:-   iv)    2,3-dichloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole;-   v)    2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;    or-   vi)    2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

It is to be understood that when A is heteroarylene, the bridgeheadatoms joining ring A to the piperidinone ring may be heteroatoms.Therefore, for example, the definition of

when A is heteroarylene encompasses the structures

It is to be understood that, where optional substitution on alkyl orcycloalkyl groups in R³, R⁹ and R¹⁰ (as defined hereinbefore orhereinafter) allows two hydroxy substituents on the alkyl or cycloalkylgroup, or one hydroxy substituent and a second substituent linked by aheteroatom (for example alkoxy), then these two substituents are notsubstituents on the same carbon atom of the alkyl or cycloalkyl group.

In another aspect, the invention relates to compounds of formula (1) ashereinabove defined or to a pharmaceutically acceptable salt.

In another aspect, the invention relates to compounds of formula (1) ashereinabove defined or to a pro-drug thereof. Suitable examples ofpro-drugs of compounds of formula (I) are in-vivo hydrolysable esters ofcompounds of formula (1). Therefore in another aspect, the inventionrelates to compounds of formula (1) as hereinabove defined or to anin-vivo hydrolysable ester thereof.

It is to be understood that, insofar as certain of the compounds offormula (1) defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses glycogen phosphorylase inhibition activity. The synthesis ofoptically active forms may be carried out by standard techniques oforganic chemistry well known in the art, for example by synthesis fromoptically active starting materials or by resolution of a racemic form.Similarly, the above-mentioned activity may be evaluated using thestandard laboratory techniques referred to hereinafter.

Within the present invention it is to be understood that a compound ofthe formula (1) or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form which hasglycogen phosphorylase inhibition activity and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.The formulae drawings within this specification can represent only oneof the possible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

It is also to be understood that certain compounds of the formula (1)and salts thereof can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which have glycogenphosphorylase inhibition activity.

It is also to be understood that certain compounds of the formula (1)may exhibit polymorphism, and that the invention encompasses all suchforms which possess glycogen phosphorylase inhibition activity.

The present invention relates to the compounds of formula (1) ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula (1) and their pharmaceutically acceptable salts.Pharmaceutically acceptable salts of the invention may, for example,include acid addition salts of the compounds of formula (1) ashereinbefore defined which are sufficiently basic to form such salts.Such acid addition salts include for example salts with inorganic ororganic acids affording pharmaceutically acceptable anions such as withhydrogen halides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid.Suitable salts include hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,acetates, benzoates, citrates, maleates, fumarates, succinates, lactatesand tartrates. In addition where the compounds of formula (I) aresufficiently acidic, pharmaceutically acceptable salts may be formedwith an inorganic or organic base which affords a pharmaceuticallyacceptable cation. Such salts with inorganic or organic bases includefor example an alkali metal salt, such as a sodium or potassium salt, analkaline earth metal salt such as a calcium or magnesium salt, anammonium salt or for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The compounds of the invention may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the invention. A prodrug may be used to alter or improve thephysical and/or pharmacokinetic profile of the parent compound and canbe formed when the parent compound contains a suitable group orsubstituent which can be derivatised to form a prodrug. Examples ofpro-drugs include in-vivo hydrolysable esters of a compound of theinvention or a pharmaceutically-acceptable salt thereof.

Various forms of prodrugs are known in the art, for examples see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in vivo hydrolysable ester of a compound of formula (1) containingcarboxy or hydroxy group is, for example a pharmaceutically acceptableester which is cleaved in the human or animal body to produce the parentacid or alcohol.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically-acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in-vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection ofin-vivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example acetyl; benzoyl; phenylacetyl; substitutedbenzoyl and phenylacetyl, C₁₋₁₀alkoxycarbonyl (to give alkyl carbonateesters), for example ethoxycarbonyl; di-(C₁₋₄)alkylcarbamoyl andN-(di-(C₁₋₄)alkylaminoethyl)-N—(C₁₋₄)alkylcarbamoyl (to givecarbamates); di-(C₁₋₄)alkylaminoacetyl and carboxyacetyl. Examples ofring substituents on phenylacetyl and benzoyl include aminomethyl,(C₁₋₄)alkylaminomethyl and di-((C₁₋₄)alkyl)aminomethyl, and morpholinoor piperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring. Other interestingin-vivo hydrolysable esters include, for example,R^(A)C(O)O(C₁₋₆)alkyl-CO—, wherein R^(A) is for example,benzyloxy-(C₁₋₄)alkyl, or phenyl). Suitable substituents on a phenylgroup in such esters include, for example,4-(C₁₋₄)piperazino-(C₁₋₄)alkyl, piperazino-(C₁₋₄)alkyl andmorpholino-(C₁-C₄)alkyl.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for the straightchain version only and references to individual branched-chain alkylgroups such as t-butyl are specific for the branched chain version only.For example, “C₁₋₄alkyl” includes methyl, ethyl, propyl, isopropyl andt-butyl and examples of “C₁₋₆alkyl” include the examples of “C₁₋₄alkyl”and additionally pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl. Ananalogous convention applies to other generic terms, for example“C₂₋₄alkenyl” includes vinyl, allyl and I-propenyl and examples of“C₂₋₆alkenyl” include the examples of “C₂₋₄alkenyl” and additionallyI-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl,1-pentenyl, 3-pentenyl and 4-hexenyl. Examples of “C₂₋₄alkynyl” includesethynyl, 1-propynyl and 2-propynyl and examples of “C₂₋₆alkynyl” includethe examples of “C₂₋₄alkynyl” and additionally 3-butynyl, 2-pentynyl and1-methylpent-2-ynyl.

The term “hydroxyC₁₋₄alkyl” includes hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxyisopropyl and hydroxybutyl. The term“hydroxyethyl” includes 1-hydroxyethyl and 2-hydroxyethyl. The term“hydroxypropyl” includes 1-hydroxypropyl, 2-hydroxypropyl and3-hydroxypropyl and an analogous convention applies to terms such ashydroxybutyl. The term “dihydroxyC₁₋₄alkyl” includes dihydroxyethyl,dihydroxypropyl, dihydroxyisopropyl and dihydroxybutyl. The term“dihydroxypropyl” includes 1,2-dihydroxypropyl and 1,3-dihydroxypropyl.An analogous convention applies to terms such as dihydroxyisopropyl anddihydroxybutyl.

The term “halo” refers to fluoro, chloro, bromo and iodo. The term“dihalo C₁₋₄alkyl” includes difluoromethyl and dichloromethyl. The term“trihalo C₁₋₄alkyl” includes trifluoromethyl.

Examples of “5- and 6-membered cyclic acetals and mono- and di-methylderivatives thereof” are:

-   1,3-dioxolan-4-yl, 2-methyl-1,3-dioxolan-4-yl,    2,2-dimethyl-1,3-dioxolan-4-yl; 2,2-dimethyl-1,3-dioxan-4-yl;    2,2-dimethyl-1,3-dioxan-5-yl; 1,3-dioxan-2-yl.

Examples of “C₁₋₄alkoxy” include methoxy, ethoxy, propoxy andisopropoxy. Examples of “C₁₋₆alkoxy” include the examples of“C₁₋₄alkoxy” and additionally butyloxy, t-butyloxy, pentoxy and1,2-(methyl)₂propoxy. Examples of “C₁₋₄alkanoyl” include formyl, acetyland propionyl. Examples of “C₁₋₆alkanoyl” include the example of“C₁₋₄alkanoyl” and additionally butanoyl, pentanoyl, hexanoyl and1,2-(methyl)₂propionyl. Examples of “C₁₋₄alkanoyloxy” are formyloxy,acetoxy and propionoxy. Examples of “C₁₋₆alkanoyloxy” include theexamples of “C₁₋₄alkanoyloxy” and additionally butanoyloxy,pentanoyloxy, hexanoyloxy and 1,2-(methyl)₂propionyloxy. Examples of“N—(C₁₋₄alkyl)amino” include methylamino and ethylamino. Examples of“N—(C₁₋₆alkyl)amino” include the examples of “N—(C₁₋₄alkyl)amino” andadditionally pentylamino, hexylamino and 3-methylbutylamino. Examples of“N,N—(C₁₋₄alkyl)₂amino” include N,N-(methyl)₂amino, N,N-(ethyl)₂aminoand N-ethyl-N-methylamino. Examples of “N,N—(C₁₋₆alkyl)₂amino” includethe example of “N,N—(C₁₋₄alkyl)₂amino” and additionallyN-methyl-N-pentylamino and N,N-(pentyl)₂amino. Examples of“N—(C₁₋₄alkyl)carbamoyl” are methylcarbamoyl and ethylcarbamoyl.Examples of “N—(C₁₋₆alkyl)carbamoyl” are the examples of“N—(C₁₋₄alkyl)carbamoyl” and additionally pentylcarbamoyl,hexylcarbamoyl and 1,2-(methyl)₂propylcarbamoyl. Examples of“N,N—(C₁₋₄alkyl)₂carbamoyl” are N,N-(methyl)₂carbamoyl,N,N-(ethyl)₂carbamoyl and N-methyl-N-ethylcarbamoyl. Examples of“N,N—(C₁₋₆alkyl)₂carbamoyl” are the examples of “NN—(C₁₋₄alkyl)₂carbamoyl” and additionally N,N-(pentyl)₂carbamoyl,N-methyl-N-pentylcarbamoyl and N-ethyl-N-hexylcarbamoyl. Examples of“N—(C₁₋₄alkyl)sulphamoyl” are N-(methyl)sulphamoyl andN-(ethyl)sulphamoyl. Examples of “N—(C₁₋₆alkyl)sulphamoyl” are theexamples of “N—(C₁₋₄alkyl)sulphamoyl” and additionallyN-pentylsulphamoyl, N-hexylsulphamoyl and 1,2-(methyl)₂propylsulphamoyl.Examples of “N,N—(C₁₋₄alkyl)₂sulphamoyl” are N,N-(methyl)₂sulphamoyl,N,N-(ethyl)₂sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of“N,N—(C₁₋₆alkyl)₂sulphamoyl” are the examples of“N,N—(C₁₋₄alkyl)₂sulphamoyl” and additionally N,N-(pentyl)₂sulphamoyl,N-methyl-N-pentylsulphamoyl and N-ethyl-N-hexylsulphamoyl.

Examples of “cyano(C₁₋₄)alkyl” are cyanomethyl, cyanoethyl andcyanopropyl. Examples of “C₅₋₇cycloalkyl” are cyclopentyl, cyclohexyland cycloheptyl. Examples of “C₃₋₈cycloalkyl” and “C₃₋₇cycloalkyl”include “C₅₋₇cycloalkyl, cyclopropyl, cyclobutyl and cyclooctyl.Examples of “C₃₋₆cycloalkyl” inclulde cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “aminoC₁₋₄alkyl” includes aminomethyl, aminoethyl, aminopropyl,aminoisopropyl and aminobutyl. The term “aminoethyl” includes1-aminoethyl and 2-aminoethyl. The term “aminopropyl” includes1-aminopropyl, 2-aminopropyl and 3-aminopropyl and an analogousconvention applies to terms such as aminoethyl and aminobutyl.

The term “sulfo” means HOSO₂—. The term “sulfino” means HO₂S—.

Examples of “C₁₋₆alkylS(O)_(a) (wherein a is 0 to 2)” includemethylthio, ethylthio, propylthio, methanesulphinyl, ethanesulphinyl,propanesulphinyl, mesyl, ethanesulphonyl, propanesulphonyl,isopropanesulphonyl, pentanesulphonyl and hexanesulphonyl.

Examples of “C₁₋₄alkylS(O)_(b) (wherein b is 0, 1 or 2)” includemethylthio, ethylthio, propylthio, methanesulphinyl, ethanesulphinyl,propanesulphinyl, mesyl, ethanesulphonyl, propanesulphonyl andisopropanesulphonyl.

Examples of “C₃₋₆cycloalkylS(O)_(b) (wherein b is 0, 1 or 2)” includecyclopropylthio, cyclopropylsulphinyl, cyclopropylsulphonyl,cyclobutylthio, cyclobutylsulphinyl, cyclobutylsulphonyl,cyclopentylthio, cyclopentylsulphinyl and cyclopentylsulphonyl.

Examples of “arylS(O)_(b) (wherein b is 0, 1 or 2)” include phenylthio,phenylsulphinyl and phenylsulfonyl. Examples of “benzylS(O)_(b) (whereinb is 0,1 or 2)” inculde benzylthio, benzylsulfinyl and benzylsulfonyl.Examples of “heterocyclylS(O)_(b) (wherein b is 0, 1 or 2)” includepyridylthio, pyridylsulfinyl, pyridylsulfonyl, imidazolylthio,imidazolylsulfinyl, imidazolylsulfonyl, pyrimidinylthio,pyrimidinylsufinyl, pyrimidinylsulfonyl, piperidylthio,piperidylsulfinyl and piperidylsulfonyl.

Examples of “C₁₋₆alkoxycarbonyl” include methoxycarbonyl,ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of“C₁₋₆alkoxycarbonylamino” include methoxycarbonylamino,ethoxycarbonylamino, n- and t-butoxycarbonylamino. Examples of“C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino” includemethylsulphonyl-N-methylamino, ethylsulphonyl-N-methylamino andpropylsulphonyl-N-ethylamino. Examples of “C₁₋₆alkylsulphonylamino”include methylsulphonylamino, ethylsulphonylamino andpropylsulphonylamino. Examples of “C₁₋₆alkanoylamino” include formamido,acetamido and propionylamino.

Examples of “C₁₋₄alkoxyC₁₋₄alkoxy” are methoxymethoxy, ethoxymethoxy,ethoxyethoxy and methoxyethoxy. Examples of “hydroxyC₁₋₄alkoxy” arehydroxyethoxy and hydroxypropoxy. Examples of “hydroxypropoxy” are1-hydroxypropoxy, 2-hydroxypropoxy and 3-hydroxypropoxy.

Where optional substituents are chosen from “0, 1, 2 or 3” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups. An analogous conventionapplies to substituents chose from “0, 1 or 2” groups and “1 or 2”groups.

“Heterocyclyl” is a saturated, partially saturated or unsaturated,optionally substituted monocyclic ring containing 5 to 7 atoms of which1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen,which may, unless otherwise specified, be carbon or nitrogen linked,wherein a —CH₂— group can optionally be replaced by a —C(O)— and a ringsulphur atom may be optionally oxidised to form the S-oxide(s). Examplesand suitable values of the term “heterocyclyl” are morpholino,morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl,imidazolyl, thiazolyl, thienyl, dioxolanyl, thiadiazolyl, piperazinyl,isothiazolidinyl, triazolyl, tetrazolyl, pyrrolidinyl, 2-oxazolidinonyl,5-isoxazolonyl, thiomorpholino, pyrrolinyl, homopiperazinyl,3,5-dioxapiperidinyl, 3-oxopyrazolin-5-yl, tetrahydropyranyl,tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl,1,1-dioxotetrahydrothiopyranyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-oxopyrrolidyl,4-oxothiazolidyl, furyl, thienyl, oxazolyl, and oxadiazolyl.

Suitably a “heterocyclyl” is morpholino, morpholinyl, piperidino,piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl,thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl,tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-oxopyrrolidyl,4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and1,2,4-oxadiazolyl.

Conveniently “heterocyclyl” is oxazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl, tetrazolyl, thizoyl, thiadiazolyl, pyridyl,imidazolyl, furyl, thienyl, morpholine, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, pyrazolinyl, and piperazinyl.

Suitable optional substituents for “heterocyclyl” as a saturated orpartially saturated ring are 1, 2 or 3 substituents independentlyselected from halo, cyano, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy andC₁₋₄alkylS(O)_(b) (wherein b is 0, 1 or 2). Further suitablesubstituents for “heterocyclyl” as a saturated or partially saturatedring are 1, 2 or 3 substituents independently selected from fluoro,chloro, cyano, hydroxy, methyl, ethyl, methoxy, methylthio,methylsulfinyl and methylsulfonyl.

Suitable optional susbtituents for “heterocyclyl” as an unsaturated ringare 1, 2 or 3 substituents independently selected from halo, cyano,nitro, amino, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b) (whereinb is 0, 1 or 2), N—(C₁₋₄alkyl)amino and N,N—(C₁₋₄alkyl)₂amino. Furthersuitable optional susbtituents for “heterocyclyl” as an unsaturated ringare 1, 2 or 3 substituents independently selected from fluoro, chloro,cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl,methoxy, methylthio, methylsulfinyl and methylsulfonyl.

Examples of “(heterocyclyl)C₁₋₄alkyl” are morpholinomethyl,morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl,piperidinoethyl, piperidylmethyl, piperidylethyl, imidazolylmethyl,imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4-oxadiazolylmethyl,1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl,pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl,pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and piperazinylethyl.

Examples of “aryl” are optionally substituted phenyl and naphthyl.

Examples of “aryl(C₁₋₄)alkyl” are benzyl, phenethyl, naphthylmethyl andnaphthylethyl.

Suitable optional substituents for “aryl” groups are 1, 2 or 3substituents independently selected from halo, cyano, nitro, amino,hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b) (wherein b is 0, 1 or2), N—(C₁₋₄alkyl)amino and N,N—(C₁₋₄alkyl)₂amino. Further suitableoptional susbtituents for “aryl” groups are 1, 2 or 3 substituentsindependently selected from fluoro, chloro, cyano, nitro, amino,methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio,methylsulfinyl and methylsulfonyl.

“Heteroarylene” is a diradical of a heteroaryl group. A heteroaryl groupis an aryl, monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or4 ring atoms are chosen from nitrogen, sulphur or oxygen. Examples ofheteroarylene are oxazolylene, oxadiazolylene, pyridylene,pyrimidinylene, imidazolylene, triazolylene, tetrazolylene,pyrazinylene, pyridazinylene, pyrrolylene, thienylene and furylene.

Suitable optional substituents for heteroaryl groups, unless otherwisedefined, are 1, 2 or 3 substituents independently selected from halo,cyano, nitro, amino, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b)(wherein b is 0, 1 or 2), N—(C₁₋₄alkyl)amino and N,N—(C₁₋₄alkyl)₂amino.Further suitable optional susbtituents for “heteroaryl” groups are 1, 2or 3 substituents independently selected from fluoro, chloro, cyano,nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl,methoxy, methylthio, methylsulfinyl and methylsulfonyl.

Preferred values of A, R¹, R², R³, R⁴, R⁵ and n are as follows. Suchvalues may be used where appropriate with any of the definitions,claims, aspects or embodiments defined hereinbefore or hereinafter.

In one embodiment of the invention are provided compounds of formula(1), in an alternative embodiment are providedpharmaceutically-acceptable salts of compounds of formula (1), in afurther alternative embodiment are provided in-vivo hydrolysable estersof compounds of formula (1), and in a further alternative embodiment areprovided pharmaceutically-acceptable salts of in-vivo hydrolysableesters of compounds of formula (1).

In one aspect of the present invention there is provided a compound offormula (1) as depicted above wherein R⁴ and R⁵ are together—S—C(R⁶)═C(R⁷)—.

In another aspect of the invention R⁴ and R⁵ are together—C(R⁷)═C(R⁶)—S—.

In a further aspect of the invention, R⁶ and R⁷ are independentlyselected from hydrogen, halo or C₁₋₆alkyl.

Preferably R⁶ and R⁷ are independently selected from hydrogen, chloro,bromo or methyl.

Particularly R⁶ and R⁷ are independently selected from hydrogen orchloro.

More particularly one of R⁶ and R⁷ is chloro.

In one embodiment, one of R⁶ and R⁷ is chloro and the other is hydrogen.

In another embodiment, both R⁶ and R⁷ are chloro.

In one aspect of the invention A is phenylene.

In another aspect of the invention A is heteroarylene.

Preferably A is selected from phenylene, pyridylene, pyrimidinylene,pyrrolylene, imidazolylene, triazolylene, tetrazolylene, oxazolylene,oxadiazolylene, thienylene and furylene.

In one aspect of the invention n is 0 or 1.

In one aspect preferably n is 1.

In another aspect, preferably n is 0.

When n is 2, and the two R¹ groups, together with the carbon atoms of Ato which they are attached, form a 4 to 7 membered ring, optionallycontaining 1 or 2 heteroatoms independently selected from O, S and N,conveniently such a ring is a 5 or 6 membered ring containing two Oatoms (ie a cyclic acetal). When the two R¹ groups together form such acyclic acetal, preferably it is not substituted. Most preferably the twoR¹ groups together are the group —O—CH₂—O—.

In another aspect of the present invention R¹ is selected from halo,nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl andC₁₋₄alkoxy.

In a further aspect R¹ is selected from halo, nitro, cyano, hydroxy,fluoromethyl, difluoromethyl, trifluoromethyl, —S(O)_(b)C₁₋₄alkyl(wherein b is 0, 1 or 2), C₁₋₄alkyl and C₁₋₄alkoxy.

In a further aspect R¹ is selected from halo, nitro, cyano, hydroxy,fluoromethyl, difluoromethyl, trifluoromethyl, —S(O)_(b)Me (wherein b is0, 1 or 2), methyl and methoxy.

In a further aspect, R¹ is C₁₋₄alkyl.

Preferably R¹ is selected from halo and C₁₋₄alkoxy.

In another embodiment preferably R¹ is selected from fluoro, chloro,methyl, ethyl, methoxy and —O—CH₂—O—.

In one aspect of the invention

is a single bond.

In another aspect of the invention

is a double bond.

In one aspect of the invention R² is hydrogen. In another aspect of theinvention R² is carboxy. In another aspect of the invention R² ishydroxy.

Preferably R² is hydrogen.

Suitable values for R³ as heterocyclyl are morpholino, morpholinyl,piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl,thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl,1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl,homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl,2-oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl,1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl, tetrahydrothiopyranyl,1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl.

More suitable values for R³ as heterocyclyl are pyridyl, pyrimidinyl andimidazolyl.

Further suitable values for R³ as heterocyclyl aretetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl,1,1-dioxotetrahydrothiopyranyl.

In one aspect of the invention R³ is selected from hydrogen, hydroxy,C₁₋₄alkoxy,

-   C₁₋₄alkanoyl, carbamoyl, C₃₋₇cycloalkyl (optionally substituted with    1 or 2 hydroxy groups, cyano(C₁₋₄)alkyl, morpholino, morpholinyl,    piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl,    thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl,    1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino,    pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl,    pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl,    4-oxopydridyl, 2-oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl,    oxazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl,    tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl, 1    μl-dioxotetrahydrothiopyranyl and C₁₋₄alkyl (optionally substituted    by 1 or 2 R⁸ groups);    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl (optionally substituted by 1 or 2 R¹³ groups),        C₃₋₇cycloalkyl (optionally substituted by 1 or 2 hydroxy        groups), cyano(C₁₋₄)alkyl, trihalo C₁₋₄alkyl, aryl, heterocyclyl        and heterocyclyl(C₁₋₄alkyl);        or    -   R⁹ and R¹⁰ together with the nitrogen to which they are attached        form a 4- to 6-membered ring where the ring is optionally        substituted on carbon by 1 or 2 substituents selected from oxo,        hydroxy, carboxy, halo, nitro, cyano, carbonyl and C₁₋₄alkoxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;    -   R⁸ is independently selected from hydroxy, C₁₋₄alkoxyC₁₋₄alkoxy,        hydroxyC₁₋₄alkoxy, 5- and 6-membered cyclic acetals and mono-        and di-methyl derivatives thereof, aryl, heterocyclyl,        C₃₋₇cycloalkyl, C₁₋₄alkanoyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b)—        (wherein b is 0, 1 or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is        0, 1 or 2), arylS(O)_(b)— (wherein b is 0, 1 or 2),        heterocyclylS(O)_(b)— (wherein b is 0, 1 or 2), benzylS(O)_(b)—        (wherein b is 0, 1 or 2), —N(OH)CHO, —C(═N—OH)NH₂,        —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂,        —C(═N—OH)NHC₃₋₆cycloalkyl, —C(—N—OH)N(C₃₋₆cycloalkyl)₂,        —COCOOR⁹, —C(O)N(R⁹)(R¹⁰), —NHC(O)R⁹, —C(O)NHSO₂(C₁₋₄alkyl),        —NHSO₂R⁹, (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹, (R⁹)(R¹⁰)N— and —COOR⁹;    -   R¹³ is selected from hydroxy, halo, trifluoromethyl and        C₁₋₄alkoxy;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl and hydroxyC₁₋₄alkyl.

In a further aspect of the invention R³ is selected from cyanoC₁₋₄alkyland C₁₋₄alkyl (optionally substituted by 1 or 2 of R⁸ groups);

-   -   R⁸ is independently selected from hydroxy, phenyl,        2,2-dimethyl-1,3-dioxolan-4-yl; 2,2-dimethyl-1,3-dioxan-4-yl;        2,2-dimethyl-1,3-dioxan-5-yl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl,        pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl,        tetrahydrothiopyranyl and tetrahydrothienyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl, C₁₋₄AalkylS(O)_(b)— (wherein b is 0, 1 or 2),        —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me, —C(═N—OH)NH₂,        —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl optionally substituted with R¹³ (wherein R¹³ is        C₁₋₄alkoxy or hydroxy); or    -   R⁹ and R¹⁰ together with the nitrogen to which they are attached        form a 4- to 6-membered ring where the ring may be optionally        substituted on carbon by 1 or 2 hydroxy groups or carboxy        groups), or the ring may be optionally substituted on two        adjacent carbons by —O—CH₂—O— to form a cyclic acetal wherein        one or both of the hydrogens of the —O—CH₂—O— group may be        replaced by a methyl.

In a further aspect of the invention R³ is selected from cyanoC₁₋₄alkyland C₁₋₄alkyl (optionally substituted by 1 or 2 R⁸ groups);

-   -   R⁸ is independently selected from hydroxy,        2,2-dimethyl-1,3-dioxolan-4-yl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, tetrazolyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,        C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰),        —COOR⁹, —C(O)NHSO₂Me, —C(═N—OH)NH₂;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl optionally substituted with R¹³ (wherein R¹³ is        C₁₋₄alkoxy or hydroxy); or    -   R⁹ and R¹⁰ together with the nitrogen to which they are attached        form a 4- to 6-membered ring selected from piperidine, 4-hydroxy        piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the        dimethylacetal of 3,4-dihydroxypyrrolidine.

In yet a further aspect of the invention R³ is selected fromhydroxypropyl, 2-hydroxybutyl, 3-hydroxy-2-hydroxymethyl-propyl,2,3-dihydroxypropyl, 1,3-dihydroxyprop-2-yl,(2,2-dimethyl-1,3-dioxolan-4-yl)methyl,(2,2-dimethyl-1,3-dioxan-4-yl)methyl,(2,2-dimethyl-1,3-dioxan-5-yl)methyl, (2-oxo-1,3-dioxan-5-yl)methyl,cyanomethyl, butanoyl, methoxyethyl,(3-hydroxypiperidino)carbonylmethyl, 1,2,4-oxadiazolylmethyl,(5-oxo)-1,2,4-oxadiazolylmethyl, (5-methyl)-1,2,4-oxadiazolylmethyl,(2-amino)-1,3,4-oxadiazolylmethyl, tetrazolylmethyl,(3,4-dihydroxypyrrolidinyl)carbonylmethyl,[(3,4-dihydroxypyrrolidinyl)carbonylmethyl]dimethylacetal,methylthioethyl, methanesulfinylethyl, methanesulfonylethyl,N-methanesulfonamidocarbonylmethyl, N-methanesulfonamidocarbonylethyl,N-(1,3-dihydroxyprop-2-yl)carbamoylmethyl, 2-(dimethylamino)ethyl,2-hydroxy-3-(dimethylamino)propyl, amino(N-hydroxy)iminomethyl,methoxycarbonylmethyl, hydroxymethylcarbonylmethyl, carboxymethyl,carbamoylmethyl, (dimethylcarbamoyl)methyl, (methylcarbamoyl)methyl,(methylcarbamoyl)ethyl, (hydroxycarbamoyl)methyl,(hydroxyethylcarbamoyl)methyl, and (methoxyethylcarbamoyl)methyl,acetylaminoethyl, trifluoroacetylaminoethyl,N-(pyrid-4-yl)carbamoylmethyl, N-(pyrid-2-yl)carbamoylmethyl,N-(3-methyl-pyrid-2-yl)carbamoylmethyl,N-(6-methyl-pyrid-2-yl)carbamoylmethyl,N-(3-hydroxy-pyrid-2-yl)carbamoylmethyl,N-(6-fluoro-pyrid-2-yl)carbamoylmethyl,N-(6-bromo-pyrid-2-yl)carbamoylmethyl,N-(6-fluoro-pyrid-3-yl)carbamoylmethyl,N-(6-chloro-pyrid-3-yl)carbamoylmethyl,N-(N-methyl-imidazol-3-yl)carbamoylmethyl,N-(imidazol-2-ylmethyl)carbamoylmethyl,N-(tetrazol-5-ylmethyl)carbamoylmethyl,N-(4-methyl-thiazol-2-yl)carbamoylmethyl,N-(1,3,4-thiadiazol-2-yl)carbamoylmethyl,N-(5-methyl-1,3,4-thiadiazol-2-yl)carbamoylmethyl,N-(5-ethyl-1,3,4-thiadiazol-2-yl)carbamoylmethyl,N-(4-cyano-pyridazin-3-yl)carbamoylmethyl,N-(6-chloro-pyridazin-3-yl)carbamoylmethyl,N-(2,4-dimethyl-2H-pyridazin-3-yl)carbamoylmethyl,N-(2-ethyl-2H-pyridazin-3-yl)carbamoylmethyl,N-(pyrazin-2-ylmethyl)carbamoylmethyl,N-(pyrimidin-4-yl)carbamoylmethyl,N-(2-hydroxy-pyrimidin-4-yl)carbamoylmethyl,N-(4-hydroxy-pyrimidin-2-yl)carbamoylmethyl,N-(N-methylpyrazol-3-yl)carbamoylmethyl,N-(5-ethylpyrazol-3-yl)carbamoylmethyl andN-(5-oxo-2H-pyrazol-3-yl)carbamoylmethyl.

In yet a further aspect of the invention R³ is selected from hydrogen,hydroxyethyl, hydroxypropyl, 2-hydroxybutyl,3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl,(2,2-dimethyl-1,3-dioxolan-4-yl)methyl,(2,2-dimethyl-1,3-dioxan-4-yl)methyl,(2,2-dimethyl-1,3-dioxan-5-yl)methyl, (2-oxo-1,3-dioxan-5-yl)methyl,cyanomethyl, butanoyl, methoxyethyl,(3-hydroxypiperidino)carbonylmethyl, 1,2,4-oxadiazolylmethyl,(5-oxo)-1,2,4-oxadiazolylmethyl, (5-methyl)-1,2,4-oxadiazolylmethyl,(2-amino)-1,3,4-oxadiazolylmethyl, tetrazolylmethyl,(3,4-dihydroxypyrrolidinyl)carbonylmethyl,[(3,4-dihydroxypyrrolidinyl)carbonylmethyl]dimethylacetal,methylthioethyl, methanesulfinylethyl, methanesulfonylethyl,N-methanesulfonamidocarbonylmethyl,N-(1,3-dihydroxyprop-2-yl)carbamoylmethyl, 2-(dimethylamino)ethyl,2-hydroxy-3-(dimethylamino)propyl, amino(N-hydroxy)iminomethyl,methoxycarbonylmethyl, carboxymethyl, carbamoylmethyl,(dimethylcarbamoyl)methyl, (methylcarbamoyl)methyl,(methylcarbamoyl)ethyl, (hydroxycarbamoyl)methyl,(hydroxyethylcarbamoyl)methyl, and (methoxyethylcarbamoyl)methyl.

In yet a further aspect of the invention R³ is selected from hydrogen,hydroxyethyl, hydroxypropyl, 2-hydroxybutyl,3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl, carbamoylmethyl,(dimethylcarbamoyl)methyl, (methylcarbamoyl)methyl,(methylcarbamoyl)ethyl, (hydroxycarbamoyl)methyl,(hydroxyethylcarbamoyl)methyl, (methoxyethylcarbamoyl)methyl,amino(N-hydroxy)iminomethyl, methanesulfinylethyl, andmethanesulfonylethyl.

In one aspect, one of R⁹ and R¹⁰ is hydrogen and the other is selectedfrom heterocyclyl and heterocyclyl(C₁₋₄alkyl). Conveniently R⁹ or R¹⁰ asheterocyclyl and heterocyclyl(C₁₋₄alkyl) is selected from oxazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazoyl,thiadiazolyl, pyridyl, imidazolyl, furyl, thienyl, morpholine,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, piperazinyl,morpholinomethyl, morpholinethyl, morpholinylmethyl, morpholinylethyl,piperidinomethyl, piperidinoethyl, piperidylmethyl, piperidylethyl,tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl,1,1-dioxotetrahydrothiopyranyl, imidazolylmethyl, imidazolylethyl,oxazolylmethyl, oxazolylethyl, 1,3,4-oxadiazolylmethyl,1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl,pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl,pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and piperazinylethyl;wherein the heterocylic ring is optional substituted on any availableatom by 1, 2 or 3 substituents independently selected from halo, cyano,hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkylS(O)_(b) (wherein b is 0, 1or 2), and additionally when the heterocyclyl ring is a heteroaryl ring,further suitable optional substituents are selected from nitro, amino,N—(C₁₋₄alkyl)amino and N,N—(C₁₋₄alkyl)₂amino, and/or wherein anyheterocyclic ring is optionally oxidised such that a —CH₂— group isreplaced by a —C(O)— and/or a ring sulphur atom is oxidised to form theS-oxide(s).

A preferred class of compound is of the formula (1) wherein;

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is halo;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups);    -   R⁸ is independently selected from hydroxy, C₃₋₇cycloalkyl,        phenyl, 2,2-dimethyl-1,3-dioxolan-4-yl;        2,2-dimethyl-1,3-dioxan-4-yl; 2,2-dimethyl-1,3-dioxan-5-yl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1        or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2),        arylS(O)_(b)— (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)—        (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me,        —C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl,        —C(═N—OH)N(C₁₋₄alkyl)₂—N(OH)CHO, —COCOOR⁹, —NHC(O)R⁹,        (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy, and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl and hydroxyC₁₋₄alkyl;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof; with the proviso that the compound of formula (1)        is not

-   i.    2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

Another preferred class of compounds is of formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is chloro;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        R⁸ groups);    -   R⁸ is independently selected from hydroxy, phenyl,        2,2-dimethyl-1,3-dioxolan-4-yl; 2,2-dimethyl-1,3-dioxan-4-yl;        2,2-dimethyl-1,3-dioxan-5-yl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl,        pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl,        tetrahydrothiopyranyl and tetrahydrothienyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1 or 2),        C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2), arylS(O)_(b)—        (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)— (wherein b is 0,        1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me, —C(═N—OH)NH₂,        —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy, and wherein R⁹ and R¹⁰ together with        the nitrogen to which they are attached form a 4- to 6-membered        ring selected from piperidine, 4-hydroxy piperidine,        pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of        3,4-dihydroxypyrrolidine;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof; with the proviso that the compound of formula (1)        is not:

-   i.    2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

Another preferred class of compounds is of formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S— or —S—C(R⁶)═C(R⁷)—;    -   R⁶ is hydrogen or chloro;    -   R⁷ is hydrogen or chloro;    -   A is phenylene;    -   n is 0;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        R⁸ groups);    -   R⁸ is independently selected from hydroxy, C₁₋₄alkylS(O)_(b)—        (wherein b is 0, 1 or 2), —NHC(O)R⁹ and —C(O)N(R⁹)(R¹⁰);    -   R⁹ and R¹⁰ are independently selected from hydrogen, C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof; with the proviso that the compound of formula (1)        is not:

-   i    2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

Another preferred class of compounds is of formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is chloro;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from groups of the formulae B and B′:        wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided        that the hydroxy group is not a substituent on the ring carbon        adjacent to the ring oxygen;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

Another preferred class of compound is of the formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —S—C(R⁶)═C(R⁷)—;    -   R⁶ is hydrogen or halo;    -   R⁷ is hydrogen or halo;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups);    -   R⁸ is independently selected from hydroxy, C₃₋₇cycloalkyl,        phenyl, 2,2-dimethyl-1,3-dioxolan-4-yl;        2,2-dimethyl-1,3-dioxan-4-yl; 2,2-dimethyl-1,3-dioxan-5-yl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1        or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2),        arylS(O)_(b)— (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)—        (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me,        —C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂,        —N(OH)CHO, —COCOOR⁹, —NHC(O)R⁹, (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹ and        —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl),C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl and hydroxyC₁₋₄alkyl;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

Another preferred class of compound is of the formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —S—C(R⁶)═C(R⁷)—;    -   R⁶ is chloro;    -   R⁷ is chloro;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups);    -   R⁸ is independently selected from hydroxy, phenyl,        2,2-dimethyl-1,3-dioxolan-4-yl; 2,2-dimethyl-1,3-dioxan-4-yl;        2,2-dimethyl-1,3-dioxan-5-yl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl,        pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl,        tetrahydrothiopyranyl and tetrahydrothienyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1 or 2),        C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2), arylS(O)_(b)—        (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)— (wherein b is 0,        1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me, —C(═N—OH)NH₂,        —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy, and wherein R⁹ and R¹⁰ together with        the nitrogen to which they are attached form a 4- to 6-membered        ring selected from piperidine, 4-hydroxy piperidine,        pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of        3,4-dihydroxypyrrolidine;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

Another preferred class of compound is of the formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —S—C(R⁶)═C(R⁷)—;    -   R⁶ is chloro;    -   R⁷ is chloro;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from groups of the formulae B and B′:        wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided        that the hydroxy group is not a substituent on the ring carbon        adjacent to the ring oxygen;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

A further preferred class of compound is of the formula (1) wherein;

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is halo;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        fluoromethyl, difluoromethyl, trifluoromethyl, C₁₋₄alkoxy and,        (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        hydroxy groups);        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof; with the proviso that the compound of formula (1)        is not

-   i.    2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

A further preferred class of compound is of the formula (1) wherein;

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is halo;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl substituted by        R⁸;    -   R⁸ is independently selected from hydroxy, C₁₋₄alkylS(O)_(b)—        (wherein b is 0, 1 or 2), —NHC(O)R⁹ and —C(O)N(R⁹)(R¹⁰);    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy, and wherein R⁹ and R¹⁰ together with        the nitrogen to which they are attached form a 4- to 6-membered        ring selected from piperidine, 4-hydroxy piperidine,        pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of        3,4-dihydroxypyrrolidine;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

Another class of compounds is of the formula (1) wherein

is a double bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S— or —S—C(R⁷)═C(R⁶)—;    -   R⁶ is hydrogen or halo;    -   R⁷ is hydrogen or halo;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups);    -   R⁸ is independently selected from hydroxy, C₃₋₇cycloalkyl,        phenyl, 2,2-dimethyl-1,3-dioxolan-4-yl;        2,2-dimethyl-1,3-dioxan-4-yl; 2,2-dimethyl-1,3-dioxan-5-yl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1        or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2),        arylS(O)_(b)— (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)—        (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me,        —C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl,        —C(═N—OH)N(C₁₋₄alkyl)₂—N(OH)CHO, —COCOOR⁹, —NHC(O)R⁹,        (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl and hydroxyC₁₋₄alkyl;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

A further class of compound is of formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S— or —S—C(R⁷)═C(R⁶)—;    -   R⁶ is hydrogen or halo;    -   R⁷ is hydrogen or hydrogen;    -   A is heteroarylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups)    -   R⁸ is independently selected from hydroxy, C₃₋₇cycloalkyl,        phenyl, 2,2-dimethyl-1,3-dioxolan-4-yl;        2,2-dimethyl-1,3-dioxan-4-yl; 2,2-dimethyl-1,3-dioxan-5-yl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1        or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2),        arylS(O)_(b)— (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)—        (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me,        —C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl,        —C(═N—OH)N(C₁₋₄alkyl)₂—N(OH)CHO, —COCOOR⁹, —NHC(O)R⁹,        (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;

-   R¹¹ is selected from hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl;    or a pharmaceutically acceptable salt or in vivo hydrolysable ester    thereof.

Yet another preferred class of compound is of the formula (1) wherein;

is a single bond;

-   -   X is N;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is halo;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups);    -   R⁸ is independently selected from hydroxy, C₃₋₇cycloalkyl,        phenyl, 2,2-dimethyl-1,3-dioxolan-4-yl;        2,2-dimethyl-1,3-dioxan-4-yl; 2,2-dimethyl-1,3-dioxan-5-yl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1        or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2),        arylS(O)_(b)— (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)—        (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me,        —C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl,        —C(═N—OH)N(C₁₋₄alkyl)₂—N(OH)CHO, —COCOOR⁹, —NHC(O)R⁹,        (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl and hydroxyC₁₋₄alkyl;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

Another preferred class of compounds is of formula (1) wherein:

is a single bond;

-   -   X is N;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is chloro;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups);    -   R⁸ is independently selected from hydroxy, phenyl,        2,2-dimethyl-1,3-dioxolan-4-yl; 2,2-dimethyl-1,3-dioxan-4-yl;        2,2-dimethyl-1,3-dioxan-5-yl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl,        pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl,        tetrahydrothiopyranyl and tetrahydrothienyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl, C₁₋₄aakylS(O)_(b)— (wherein b is 0, 1 or 2),        C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2), arylS(O)_(b)—        (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)— (wherein b is 0,        1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me, —C(═N—OH)NH₂,        —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy        or the ring may be optionally substituted on two adjacent        carbons by O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof;

Another preferred class of compound is of the formula (1) wherein:

is a single bond;

-   -   X is N;    -   R⁴ and R⁵ are together —S—C(R⁶)═C(R⁷)—;    -   R⁶ is hydrogen or halo;    -   R⁷ is hydrogen or halo;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl (optionally        substituted by 1 or 2 R⁸ groups);    -   R⁸ is independently selected from hydroxy, phenyl,        2,2-dimethyl-1,3-dioxolan-4-yl; 2,2-dimethyl-1,3-dioxan-4-yl;        2,2-dimethyl-1,3-dioxan-5-yl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl,        pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl,        tetrahydrothiopyranyl and tetrahydrothienyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1 or 2),        C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2), arylS(O)_(b)—        (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)— (wherein b is 0,        1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me, —C(═N—OH)NH₂,        —C(═N—OH)NHC X₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

A further preferred class of compound is of the formula (1) wherein;

is a single bond;

-   -   X is N;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is halo;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        hydroxy groups);        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof;

A further preferred class of compound is of the formula (1) wherein;

is a single bond;

-   -   X is N;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is halo;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from cyanoC₁₋₄alkyl, and C₁₋₄alkyl substituted by        R⁸;    -   R⁸ is independently selected from hydroxy, C₁₋₄alkylS(O)_(b)—        (wherein b is 0, 1 or 2), —NHC(O)R⁹ and —C(O)N(R⁹)(R¹⁰);    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy, and wherein R⁹ and R¹⁰ together with        the nitrogen to which they are attached form a 4- to 6-membered        ring selected from piperidine, 4-hydroxy piperidine,        pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of        3,4-dihydroxypyrrolidine;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

Another class of compounds is of the formula (1) wherein

is a double bond;

-   -   X is N;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S— or —S—C(R⁷)═C(R⁶)—;    -   R⁶ is hydrogen or halo;    -   R⁷ is hydrogen or halo;    -   A is phenylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        R⁸ groups);    -   R⁸ is independently selected from hydroxy, C₃₋₇cycloalkyl,        phenyl, 2,2-dimethyl-1,3-dioxolan-4-yl;        2,2-dimethyl-1,3-dioxan-4-yl; 2,2-dimethyl-1,3-dioxan-5-yl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1        or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2),        arylS(O)_(b)— (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)—        (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me,        —C(═N—OH)NH₂₂, —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂,        —N(OH)CHO, —COCOOR⁹, —NHC(O)R⁹, (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹ and        —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl and hydroxyC₁₋₄alkyl;        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

A further class of compound is of formula (1) wherein:

is a single bond;

-   -   X is N;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S— or —S—C(R⁷)═C(R⁶)—;    -   R⁶ is hydrogen or halo;    -   R⁷ is hydrogen or hydrogen;    -   A is heteroarylene;    -   n is 0, 1 or 2;    -   R¹ is independently selected from halo, cyano, nitro, hydroxy,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        —SMe, —SOMe, —SO₂Me and, (when n is 2) methylenedioxy;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        R⁸ groups);    -   R⁸ is independently selected from hydroxy, C₃₋₇cycloalkyl,        phenyl, 2,2-dimethyl-1,3-dioxolan-4-yl;        2,2-dimethyl-1,3-dioxan-4-yl; 2,2-dimethyl-1,3-dioxan-5-yl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1        or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1 or 2),        arylS(O)_(b)— (wherein b is 0, 1 or 2), heterocyclylS(O)_(b)—        (wherein b is 0, 1 or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me,        —C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl,        —C(═N—OH)N(C₁₋₄alkyl)₂—N(OH)CHO, —COCOOR⁹, —NHC(O)R⁹,        (R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹ and —NHSO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        phenyl, heterocyclyl, heterocyclyl(C₁₋₄alkyl), C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups) and C₁₋₄alkyl        substituted by C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together        with the nitrogen to which they are attached form 4- to        6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from hydroxy or carboxy,        or the ring may be optionally substituted on two adjacent        carbons by —O—CH₂—O— to form a cyclic acetal wherein one or both        of the hydrogens of the —O—CH₂—O— group may be replaced by a        methyl;

-   R¹¹ is selected from hydrogen, C₁₋₄alkyl and hydroxyC₁₋₄alkyl;    or a pharmaceutically acceptable salt or in vivo hydrolysable ester    thereof.

In another aspect of the invention, a preferred class of compound is ofthe formula (1) wherein;

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is halo;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, cyano, nitro,        hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl,        C₁₋₄alkoxy and R¹ is of the formula A′ or A″:         —CH₂CH(OH)(CH₂)_(u)CO₂H  (A″)        wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided        that the hydroxy group is not a substituent on the ring carbon        adjacent to the ring oxygen;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        hydroxy groups provided that when there are 2 hydroxy groups        they are not substituents on the same carbon), cyanoC₁₋₄alkyl,        and C₁₋₄alkyl [substituted by 1 or 2 R⁸ groups (provided that        when there are 2 R⁸ groups they are not substituents on the same        carbon)];    -   {R⁵ is independently selected from hydroxy, heterocyclyl,        C₁₋₄alkanoyl, C₁₋₄alkoxy, C₁₋₄alkanesulfinyl,        C₁₋₄alkanesulfonyl, —COCOOR⁹, (R⁹)(R¹⁰)NCO—, —COCH₂OR¹¹,        (R⁹)(R¹⁰)N—, —COOR⁹ and 2,2-dimethyl-1,3-dioxolan-4-yl;    -   [R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups        provided that when there are 2 hydroxy groups they are not        substituents on the same carbon) and C₁₋₄alkyl substituted by        C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together with the nitrogen        to which they are attached form 4- to 6-membered ring where the        ring is optionally substituted on carbon by 1 or 2 substituents        selected from hydroxy or carboxy;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy and        hydroxyC₁₋₄alkyl]};        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof;        with the proviso that the compound of formula (1) is not:

-   ii.    2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;    or

-   iii.    2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

In another aspect of the invention, another preferred class of compoundsis of formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —C(R⁷)═C(R⁶)—S—;    -   R⁶ is chloro;    -   R⁷ is hydrogen;    -   A is phenylene;    -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, nitro,        hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy and

-   R¹ is of the formula A′ or A″:     —CH₂CH(OH)(CH₂)_(u)CO₂H  (A″)    wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided    that the hydroxy group is not a substituent on the ring carbon    adjacent to the ring oxygen;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        hydroxy groups provided that when there are 2 hydroxy groups        they are not substituents on the same carbon), cyanoC₁₋₄alkyl,        and C₁₋₄alkyl [substituted by 1 or 2 R⁸ groups (provided that        when there are 2 R⁸ groups they are not substituents on the same        carbon)];    -   {R⁸ is independently selected from hydroxy, heterocyclyl,        C₁₋₄alkanoyl, C₁₋₄alkoxy, C₁₋₄alkanesulfinyl, C₁₋₄alkylsulfonyl,        —COCOOR⁹, (R⁹)(R¹⁰)NCO—, —COCH₂OR¹¹, (R⁹)(R¹⁰)N—, —COOR⁹ and        2,2-dimethyl-1,3-dioxolan-4-yl;    -   [R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups        provided that when there are 2 hydroxy groups they are not        substituents on the same carbon) and C₁₋₄alkyl substituted by        C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together with the nitrogen        to which they are attached form 4- to 6-membered ring where the        ring is optionally substituted on carbon by 1 or 2 substituents        selected from hydroxy or carboxy;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy and        hydroxyC₁₋₄alkyl]};        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof;        with the proviso that the compound of formula (1) is not:

-   ii.    2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;    or

-   iii.    2-chloro-5-[N—(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

In another aspect of the invention, another preferred class of compoundis of the formula (1) wherein:

is a single bond;

-   -   X is CH;    -   R⁴ and R⁵ are together —S—C(R⁶)═C(R⁷)—;    -   R⁶ is hydrogen or halo;    -   R⁷ is hydrogen or halo;    -   A is phenylene;    -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, nitro,        hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy and

-   R¹ is of the formula A′ or A″:     —CH₂CH(OH)(CH₂)_(u)CO₂H  (A″)    wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided    that the hydroxy group is not a substituent on the ring carbon    adjacent to the ring oxygen;    -   R² is hydrogen;    -   R³ is selected from C₁₋₄alkyl (optionally substituted by 1 or 2        hydroxy groups provided that when there are 2 hydroxy groups        they are not substituents on the same carbon), cyanoC₁₋₄alkyl,        and C₁₋₄alkyl [substituted by 1 or 2 R⁸ groups (provided that        when there are 2 R₈ groups they are not substituents on the same        carbon)];    -   {R⁸ is independently selected from hydroxy, heterocyclyl,        C₁₋₄alkanoyl, C₁₋₄alkoxy, C₁₋₄alkanesulfinyl, C₁₋₄alkylsulfonyl,        —COCOOR⁹, (R⁹)(R¹⁰)NCO—, —COCH₂OR¹¹, (R⁹)(R¹⁰)N—, —COOR⁹ and        2,2-dimethyl-1,3-dioxolan-4-yl;    -   [R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups        provided that when there are 2 hydroxy groups they are not        substituents on the same carbon) and C₁₋₄alkyl substituted by        C₁₋₄alkoxy and wherein R⁹ and R¹⁰ can together with the nitrogen        to which they are attached form 4- to 6-membered ring where the        ring is optionally substituted on carbon by 1 or 2 substituents        selected from hydroxy or carboxy;    -   R¹¹ is selected from hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy and        hydroxyC₁₋₄alkyl]};        or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof;        with the proviso that the compound of formula (1) is not        2,3-dichloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole.

In another aspect of the invention, preferred compounds of the inventionare any one of:

-   2-chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(carbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(N,N-dimethylcarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(N-methylcarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(N-hydroxycarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[N-(2-hydroxyethyl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrol-5-ylcarboxamide;-   2-chloro-N-[1-(2,3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[(2,2-dimethyl-1,3-dioxolan-4(S)-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(2(S),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(2(R),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno    [2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[N-(1,3-dihydroxyprop-2-yl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[N-(2-methoxyethyl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-(1-{2-[(3a,6a-cis)-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-(1-{2-[(cis)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-{1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2-chloro-N-(1-{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(methoxy)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[2-oxo-1-(1H-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-(1-{2-[(methylsulphonyl)amino]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   N-{1-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{2-oxo-1-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl]-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   N-{1-[(5-amino-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(methylthio)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(methylsulfinyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-{1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[3-(dimethylamino)-2-hydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{2-oxo-1-[(2-oxo-1,3-dioxan-5-yl)methyl]-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[3-(methylamino)-3-oxopropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[2-oxo-1-(2-oxobutyl)-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide.-   2-chloro-N-[1-(2-hydroxybutyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-[(6S)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-6-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2-chloro-N-(2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   N-(6-fluoro-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;    and-   N-(6-methoxy-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;    or a pharmaceutically acceptable salt or an in vivo hydrolysable    ester thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of:

-   2-chloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrol-5-ylcarboxamide;-   2-chloro-N-[1-(2,3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(2(S),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(2(R),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[N-(1,3-dihydroxyprop-2-yl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[N-(2-methoxyethyl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   N-{1-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-(1-{2-[(3a,6a-cis)-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-(1-{2-[(cis)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2-chloro-N-(1-{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(methylsulfinyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-{1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   2-chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2-chloro-N-{1-[3-(methylamino)-3-oxopropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;    and-   2-chloro-N-[1-(2-hydroxybutyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;    or a pharmaceutically acceptable salt or an in vivo hydrolysable    ester thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of:

-   2-chloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrol-5-ylcarboxamide;-   2-chloro-N-[1-(2(R),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;-   N-{1-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;-   2,3-dichloro-N-{1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}4H-thieno[3,2-b]pyrrole-5-carboxamide;    and-   2-chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;    or a pharmaceutically acceptable salt or an in vivo hydrolysable    ester thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (1) or a pharmaceutically acceptable salt or an invivo hydrolysable ester thereof which process (wherein A, R¹, R², R³,R⁴, R⁵, n and—are, unless otherwise specified, as defined in formula(1)) comprises of:

-   a) reacting an acid of the formula (2):    or an activated derivative thereof; with an amine of formula (3):    and thereafter if necessary:-   i) converting a compound of the formula (1) into another compound of    the formula (1);-   ii) removing any protecting groups;-   iii) forming a pharmaceutically acceptable salt or in vivo    hydrolysable ester.

Specific reaction conditions for the above reaction are as follows.

Process a) Acids of formula (2) and amines of formula (3) may be coupledtogether in the presence of a suitable coupling reagent. Standardpeptide coupling reagents known in the art can be employed as suitablecoupling reagents, or for example carbonyldiimidazole,1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride (EDCI) anddicyclohexyl-carbodiimide (DCCI), optionally in the presence of acatalyst such as 1-hydroxybenzotriazole, dimethylaminopyridine or4-pyrrolidinopyridine, optionally in the presence of a base for exampletriethylamine, di-isopropylethylamine, pyridine, or2,6-di-alkyl-pyridines such as 2,6-lutidine or2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide,dichloromethane, benzene, tetrahydroftiran and dimethylformamide. Thecoupling reaction may conveniently be performed at a temperature in therange of −40 to 40° C. Suitable activated acid derivatives include acidhalides, for example acid chlorides, and active esters, for examplepentafluorophenyl esters. The reaction of these types of compounds withamines is well known in the art, for example they may be reacted in thepresence of a base, such as those described above, and in a suitablesolvent, such as those described above. The reaction may conveniently beperformed at a temperature in the range of −40 to 40° C.

Where R³ of formula (1) contains an ester group, the conversion of acompound of the formula (1) into another compound of the formula (1) mayinvolve hydrolysis of the ester group, for example, acid or basehydrolysis, for example using lithium hydroxide. The reaction of thistype is well known in the art.

Substituted amides wherein R³ is CH₂C(O)N(R⁹)(R¹⁰) may be prepared fromthe corresponding acids by a coupling reaction using the appropriateamine in the presence of a coupling reagent, for example EDCI.Alternatively, the acid may first be converted to a mixed anhydride, byreaction with, for example, ethyl chloroformate, which is reacted withan appropriate amine to produce the substituted amide. Substitutedsulphonamides wherein R³ is CH₂C(O)NHSO₂R₉ may be prepared similarly,for instance by coupling the compounds wherein R³ is CH₂CO₂H with theappropriate substituted sulphonamide in the presence of a couplingreagent, for example EDCI.

Compounds of formula (1) wherein R³ is 2-hydroxyethyl may be prepared byreduction of the mixed anhydrides described above with, for example,lithium borohydride. Compounds of formula (1) wherein R³ is anoxadiazol-5-ylmethyl group may be prepared by reaction of the mixedanhydrides described above with an appropriately substitutedhydroxyamidine, for example N-hydroxyethanimidamide, in the presence ofa base such as N-methylmorpholine.

Compounds of formula (1) wherein R³ is a tetrazol-5-ylmethyl group maybe prepared by reaction of the corresponding compounds where R³ is acyanomethyl group with an azide, for example sodium azide, in thepresence of an amine salt, for instance triethylamine hydrochloride.Compounds of formula (1) wherein R³ is 2-amino-2-(hydroxyimino)ethyl maybe prepared by reaction of compounds wherein R³ is cyanomethyl withhydroxylamine hydrochloride in the presence of a base, for examplesodium methoxide.

Compounds of formula (1) wherein R³ is a 2-(methylsulphonyl)ethyl or2-(methylsulphinyl)ethyl group may be prepared by reaction of thecorresponding compounds where R³ is 2-methylthioethyl with an oxidisingagent, for example oxone.

Compounds of formula (1) wherein R³ is a dihydroxyalkyl group, forexample 2,3-dihydroxypropyl or 2-(hydroxymethyl)-3-hydroxypropyl may beprepared by acid hydrolysis of the corresponding compounds of formula(1) wherein R³ is a protected dihydroxyalkyl group for example(2,2-dimethyl-1,3-dioxan-5-yl)methyl,(2,2-dimethyl-1,3-dioxolan-4-yl)methyl or (2-oxo-1,3-dioxan-5-yl)methyl.

The acids of formula (2), wherein X is CH, may be prepared according toScheme 1:

Compounds of formula (2a) are commercially available or they are knowncompounds or they are prepared by processes known in the art.

The acids of the formula (2), wherein X is N, can be prepared from acompound of the formula (6):

by firstly converting the oxo group to chlorine or bromine with ahalogenating agent such as POCl₃ or POBr₃, in an inert organic solventsuch as dichloromethane in a temperature range of ambient temperature toreflux (for example see Nucleic Acid Chem. 1991, 4, 24-6), thendisplacing the chlorine or bromine group with cyanide using a cyanidesalt such as potassium cyanide, in an inert organic solvent such astoluene, benzene or xylene, optionally in the presence of a catalystsuch as 18-crown-6 (for example see J Heterocycl. Chem 2000, 37(1)119-126) and finally hydrolysing the cyano group to a carboxy group,with for example, an aqueous acid such as aqueous hydrogen chloride (forexample see Chem. Pharm. Bull. 1986, 34(9) 3635-43).

Alternatively, a compound of the formula (2) wherein X is N may beformed by reacting the compound of the formula (6) with (Cl₃CCO)₂O andCl₃CCO₂H in the presence of magnesium chloride using Cl₃CCO₂H assolvent, to form a compound of the formula (7):

and then hydrolyising the compound of the formula (7), using, forexample, aqueous sodium hydroxide, at a temperature range of ambienttemperature to reflux (for example see J Heterocycl. Chem. 1980, 17(2),381-2).

The compound of formula (6) may be prepared from a compound of formula(12) and (13) using conditions known for the Curtius rearrangement(Tetrahedron 1999, 55, 6167):

The compounds of the formula (10) and (11):

transform into compounds of the formula (12) and (13) respectively. Thistransformation either occurs spontaneously or may be induced with acidor base.

Compounds of the formula (10) and (11) may be prepared by introducing acarboxy group into a compound of the formula (8) or (9):

wherein P′ is an amino protecting group such as butoxycarbonyl.

A carboxy group is introduced into the compound of the formula (8) or(9) by reacting an alkyl lithium reagent such as n-butyl lithium, in aninert organic solvent such as THF, at low temperature, for example inthe range −10° C. to −78° C. and then forming the compound of theformula (10) or (11) as appropriate by either

-   a) reacting the resulting compound with carbon dioxide; or-   b) by reacting with DMF in the temperature range of −10° C. to    ambient temperature to form the corresponding aldehyde and oxidizing    the aldehyde to carboxy with standard reagents to give the compound    of the formula (10) or (11).

Compounds of the formula (8) and (9) may be prepared from a compound ofthe formula (14) and (15):

using conditions known for the Curtius reaction.

Compounds of the formula (14) and (15) may be prepared by oxidizing thecorresponding aldehyde using standard oxidizing reagents such aspotassium manganate or sodium periodate.

The aldehyde precursor of a compound of the formula (14) or (15) can beprepared using standard techniques known in the art. For example, manycompounds of the formula (14) or (15) may be prepared by introducing theappropriate R⁶ and R⁷ into a compound of the formula (16) or (17) asappropriate:

For example, when R⁶ and R⁷ are both chloro a compound of the formula(16) or (17) may be chlorinated with a chlorinating agent such aschlorine in the presence of aluminium chloride or iron (III) chloride,in an inert organic chlorinated solvent such as dichloromethane or1,2-dichloroethane, followed by treatment with an aqueous base, such as,aqueous sodium hydroxide. The mono chlorinated compound can be formed inthe same way.

Compounds of formula (3) may be prepared by reacting an amine of formula(4)

with R³-L where L is a suitable leaving group (for example chloro, bromoor iodo) in the presence of a base such as sodium hydride in a suitablesolvent.

Compounds of the formula (4) wherein A is phenylene and

is a single bond may be made from 3-amino-3,4-dihydroquinolin-2-(1H)-onehydrochloride (J. Med. Chem., 28, 1985, 1511-16). Compounds of theformula (4) wherein A is phenylene and

is a double bond may be prepared by the reductive cyclisation of acompound of formula (18), using for example tin (II) chloride inhydrochloric acid, followed by removal of the Boc protecting group,using for example trifluoroacetic acid. Compounds of formula (18) may beprepared by reaction of compounds of formula (19) by reaction with acompound of formula (20) in the presence of a base, for exampletetramethylguanidine. Compounds of formula (19) are commerciallyavailable or described in the literature.

Compounds of the formula (4) wherein A is heterocyclylene can beprepared from cyclisation of suitably functionalised heterocycles. Forexample, when A is pyridine,

compounds of formula (4a) and (4b) may be prepared from an appropriatelysubstituted nitro-methylpyridine or amino-pyridine according to theSchemes 2 and 3:—

Steps 1 and 2 may be carried out by the process described in Tetrahedron1998, 54(23), 6311-6318.

Step 3 may be carried out by the method described in Synthesis 1992(5),487 Assymetric hydrogenation reactions of olefins as shown in Step 4are well known (see for example, JACS 1993, 115, 10125-10138) and leadto homochiral final products.

Step 5 may alternatively be carried out by hydrolysing the ester andactivating the resulting acid with a carbodiimide such as EDCI or DCCI,or by preparing an acid chloride, or activated ester such as anN-hydroxysuccinimide ester. Suitable bases are organic base such astriethylamine or di-isopropylethylamine (DIPEA) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

In Step 6 X is a leaving group, for example Cl, Br, I, OMesyl. In Step 7alternative solvents such as dichloromethane or other acids such astrifluoroacetic acid can be used.

Steps 1, 2, 3 and 4 are described in JOC 1983, 48, 3401-3408.

The processes described above and shown in Schemes 2 and 3 may also beapplied to other isomeric pyridines or six membered heterocyclescontaining more than one nitrogen.

Compounds of the formula (4) wherein A is heteroarylene and there is abridgehead nitrogen, for example a compound of formula (4c),

may be prepared by cyclisation of a compound of the formula (21):

wherein P is an amino protecting group such as triphenylmethyl. Thistransformation is induced by heating compounds of the formula (21) toreflux in a solvent, for example, ethanol.

Compounds of the formula (21) may be prepared from a compound of theformula (22) by hydrogenation using a catalyst such as Pd/C at ambienttemperature.

Compounds of the formula (22) may be prepared from compounds of theformula (23) and (24):

using conditions known for the Mitsunobu reaction (Bull. Chem. Soc.Jpn., 1967, 40, 2380). Compounds of the formula (23) and (24) arecommercially available.

Compounds of formula (2b) may also be prepared as illustrated in Scheme4:

The conversion of compounds of formula (8) into compounds of formula(25) may be carried out by directed ortho lithiation reactions (J. Org.Chem, 2001, volume 66, 3662-3670), for example with n-butyl lithium and(CHO)N(alkyl)₂. The protecting group P′ in compounds of formula (8) mustbe suitable directing group for this reaction and may be for example—CO₂tBu. Reaction of compounds of formula (25) with LCH₂CO₂R where L isa leaving group, and replacement of the protecting group P′ with analternative P″ (for example —COalkyl) according to standard processes,gives a compound of formula (26). This may be cyclised using a base, forexample potassium carbonate or sodium methoxide.

Compounds of the formula (4) wherein A is heteroarylene and there is abridgehead heteroatom, for example, compounds of the formula (4d) may bemade by analogous chemistry to that shown for making compounds of theformula (4c).

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention, for example R¹, may beintroduced by standard aromatic substitution reactions or generated byconventional functional group modifications either prior to orimmediately following the processes mentioned above, and as such areincluded in the process aspect of the invention. Such reactions mayconvert one compound of the formula (1) into another compound of theformula (1). Such reactions and modifications include, for example,introduction of a substituent by means of an aromatic substitutionreaction, reduction of substituents, alkylation of substituents andoxidation of substituents. The reagents and reaction conditions for suchprocedures are well known in the chemical art. Particular examples ofaromatic substitution reactions include the introduction of a nitrogroup using concentrated nitric acid, the introduction of an acyl groupusing, for example, an acyl halide and Lewis acid (such as aluminiumtrichloride) under Friedel Crafts conditions; the introduction of analkyl group using an alkyl halide and Lewis acid (such as aluminiumtrichloride) under Friedel Crafts conditions; and the introduction of ahalogen group. Particular examples of modifications include thereduction of a nitro group to an amino group by for example, catalytichydrogenation with a nickel catalyst or treatment with iron in thepresence of hydrochloric acid with heating; oxidation of alkylthio toalkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Certain intermediates in the preparation of a compound of the formula(1) are novel and form another aspect of the invention.

As stated hereinbefore the compounds defined in the present inventionpossesses glycogen phosphorylase inhibitory activity. This property maybe assessed, for example, using the procedure set out below.

Assay

The activity of the compounds is determined by measuring the inhibitoryeffect of the compounds in the direction of glycogen synthesis, theconversion of glucose-1-phosphate into glycogen with the release ofinorganic phosphate, as described in EP 0 846 464 A2. The reactions werein 96well microplate format in a volume of 100 μl. The change in opticaldensity due to inorganic phosphate formation was measured at 620 nM in aLabsystems iEMS Reader MF by the general method of (Nordlie R. C andArion W. J, Methods of Enzymology, 1966, 619-625). The reaction is in 5mM HEPES (N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonicacid);4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid), 2.5 mM MgCl₂,2.25 mM ethylene glycol-bis(b-aminoethyl ether) N,N,N′,N′-tetraaceticacid, 100 mM KCl, 2 mM D-(+)-glucose pH7.2, containing 0.5 mMdithiothreitol, the assay buffer solution, with 0.1 mg type IIIglycogen, 0.15 ug glycogen phosphorylase a (GPa) from rabbit muscle and0.5 mM glucose-1-phosphate. GPa is pre-incubated in the assay buffersolution with the type III glycogen at 2.5 mg ml⁻¹ for 30 minutes. 40μlof the enzyme solution is added to 25 μl assay buffer solution and thereaction started with the addition of 25 μl 2 mM glucose-1-phosphate.Compounds to be tested are prepared in 10 μl 10% DMSO in assay buffersolution, with final concentration of 1% DMSO in the assay. Thenon-inhibited activity of GPa is measured in the presence of 10 μl 10%DMSO in assay buffer solution and maximum inhibition measured in thepresence of 30 μM CP320626 (Hoover et al (1998) J Med Chem 41, 2934-8;Martin et al (1998) PNAS 95, 1776-81). The reaction is stopped after 30min with the addition of 50 μl acidic ammonium molybdate solution, 12 ugml⁻¹ in 3.48% H₂SO₄ with 1% sodium lauryl sulphate and 10 ug ml⁻¹ascorbic acid. After 30 minutes at room temperature the absorbency at620 nm is measured.

The assay is performed at a test concentration of inhibitor of 10 μM or100 μM. Compounds demonstrating significant inhibition at one or both ofthese concentrations may be further evaluated using a range of testconcentrations of inhibitor to determine an IC₅₀, a concentrationpredicted to inhibit the enzyme reaction by 50%.

Activity is calculated as follows:—% inhibition=(1−(compound OD620−fully inhibited OD620)/(non-inhibitedrate OD620−fully inhibited OD620))*100.OD620=optical density at 620 nM.

Typical IC₅₀ values for compounds of the invention when tested in theabove assay are in the range 100 μM to 1 nM.

The activity of the compounds is alternatively determined by measuringthe inhibitory effect of the compounds on glycogen degradation, theproduction of glucose-1-phosphate from glycogen is monitored by themultienzyme coupled assay, as described in EP 0 846 464 A2, generalmethod of Pesce et al (Pesce, M A, Bodourian, S H, Harris, R C, andNicholson, J F (1977) Clinical Chemistry 23, 1171-1717). The reactionswere in 384well microplate format in a volume of 50 μl. The change influorescence due to the conversion of the co-factor NAD to NADH ismeasured at 340 nM excitation, 465 nm emission in a Tecan UltraMultifunctional Microplate Reader. The reaction is in 50 mM HEPES, 3.5mM KH₂PO₄, 2.5 mM MgCl₂, 2.5 mM ethylene glycol-bis(b-aminoethyl ether)N,N,N′,N′-tetraacetic acid, 100 mM KCl, 8 mM D-(+)-glucose pH7.2,containing 0.5 mM dithiothreitol, the assay buffer solution. Humanrecombinant liver glycogen phosphorylase a (hrl GPa) 20 nM ispre-incubated in assay buffer solution with 6.25 mM NAD, 1.25 mg typeIII glycogen at 1.25 mg ml⁻¹ the reagent buffer, for 30 minutes. Thecoupling enzymes, phosphoglucomutase and glucose-6-phosphatedehydrogenase (Sigma) are prepared in reagent buffer, finalconcentration 0.25 Units per well. 20 μl of the hrl GPa solution isadded to 10 μl compound solution and the reaction started with theaddition of 20 ul coupling enzyme solution. Compounds to be tested areprepared in 10 μl 5% DMSO in assay buffer solution, with finalconcentration of 1% DMSO in the assay. The non-inhibited activity of GPais measured in the presence of 10 μl 5% DMSO in assay buffer solutionand maximum inhibition measured in the presence of 5 mgs ml⁻¹N-ethylmaleimide. After 6 hours at 30° C. Relative Fluoresence Units(RFUs) are measured at 340 nM excitation, 465 nm emission.

The assay is performed at a test concentration of inhibitor of 10 μM or100 μM. Compounds demonstrating significant inhibition at one or both ofthese concentrations may be further evaluated using a range of testconcentrations of inhibitor to determine an IC₅₀, a concentrationpredicted to inhibit the enzyme reaction by 50%.

Activity is calculated as follows:—% inhibition=(1−(compound RFUs−fully inhibited RFUs)/(non-inhibited rateRFUs−fully inhibited RFUs))*100.

Typical IC₅₀ values for compounds of the invention when tested in theabove assay are in the range 100 μM to 1 nM. For example, Example 14gave an IC₅₀ value of 2.7 μM.

The inhibitory activity of compounds was further tested in rat primaryhepatocytes.

Rat hepatocytes were isolated by the collagenase perfusion technique,general method of Seglen (P. O. Seglen, Methods Cell Biology (1976) 1329-83). Cells were cultured on Nunclon six well culture plates in DMEM(Dulbeco's Modified Eagle's Medium) with high level of glucosecontaining 10% foetal calf serum, NEAA (non essential amino acids),Glutamine, penicillin/streptomycin ((100 units/100 ug)/ml) for 4 to 6hours. The hepatocytes were then cultured in the DMEM solution withoutfoetal calf serum and with 10 nM insulin and 10 nM dexamethasone.Experiments were initiated after 18-20 hours culture by washing thecells and adding Krebs-Henseleit bicarbonate buffer containing 2.5 mMCaCl₂ and 1% gelatin. The test compound was added and 5 minutes laterthe cells were challenged with 25 nM glucagon. The Krebs-Henseleitsolution was removed after 60 min incubation at 37° C., 95% O₂/5% CO₂and the glucose concentration of the Krebs-Henseleit solution measured.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula(1), or a pharmaceutically acceptable salt or in vivo hydrolysable esterthereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The compound of formula (1) will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0.1-100 mg/kg, andthis normally provides a therapeutically-effective dose. A unit doseform such as a tablet or capsule will usually contain, for example 1-250mg of active ingredient. Preferably a daily dose in the range of 1-50mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

The inhibition of glycogen phosphorylase activity described herein maybe applied as a sole therapy or may involve, in addition to the subjectof the present invention, one or more other substances and/ortreatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment. Simultaneous treatment may be in a singletablet or in separate tablets. For example in the treatment of diabetesmellitus chemotherapy may include the following main categories oftreatment:

-   -   1) Insulin and insulin analogues;    -   2) Insulin secretagogues including sulphonylureas (for example        glibenclamide, glipizide) and prandial glucose regulators (for        example repaglinide, nateglinide);    -   3) Insulin sensitising agents including PPARg agonists (for        example pioglitazone and rosiglitazone);    -   4) Agents that suppress hepatic glucose output (for example        metformin).    -   5) Agents designed to reduce the absorption of glucose from the        intestine (for example acarbose);    -   6) Agents designed to treat the complications of prolonged        hyperglycaemia;    -   7) Anti-obesity agents (for example sibutramine and orlistat);    -   8) Anti-dyslipidaemia agents such as, HMG-CoA reductase        inhibitors (statins, eg pravastatin); PPARα agonists (fibrates,        eg gemfibrozil); bile acid sequestrants (cholestyramine);        cholesterol absorption inhibitors (plant stanols, synthetic        inhibitors); bile acid absorption inhibitors (IBATi) and        nicotinic acid and analogues (niacin and slow release        formulations);    -   9) Antihypertensive agents such as, β blockers (eg atenolol,        inderal); ACE inhibitors (eg lisinopril); Calcium antagonists        (eg. nifedipine); Angiotensin receptor antagonists (eg        candesartan), α antagonists and diuretic agents (eg. furosemide,        benzthiazide);    -   10) Haemostasis modulators such as, antithrombotics, activators        of fibrinolysis and antiplatelet agents; thrombin antagonists;        factor Xa inhibitors; factor VIIa inhibitors); antiplatelet        agents (eg. aspirin, clopidogrel); anticoagulants (heparin and        Low molecular weight analogues, hirudin) and warfarin; and    -   11) Anti-inflammatory agents, such as non-steroidal        anti-inflammatory drugs (eg. aspirin) and steroidal        anti-inflammatory agents (eg. cortisone).

According to a further aspect of the present invention there is provideda compound of the formula (1), or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof, as defined hereinbefore, for use ina method of treatment of a warm-blooded animal such as man by therapy.

According to an additional aspect of the invention there is provided acompound of the formula (1), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined hereinbefore, for use as amedicament.

According to an additional aspect of the invention there is provided acompound of the formula (1), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined hereinbefore, for use as amedicament in the treatment of type 2 diabetes, insulin resistance,syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia orobesity in a warm-blooded animal such as man.

According to this another aspect of the invention there is provided theuse of a compound of the formula (1), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof, as defined hereinbefore inthe manufacture of a medicament for use in the treatment of type 2diabetes, insulin resistance, syndrome X, hyperinsulinaemia,hyperglucagonaemia, cardiac ischaemia or obesity in a warm-bloodedanimal such as man.

According to this another aspect of the invention there is provided theuse of a compound of the formula (1), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof, as defined hereinbefore inthe manufacture of a medicament for use in the treatment of type 2diabetes in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method of producing a glycogen phosphorylase inhibitoryeffect in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (1).

According to this further feature of this aspect of the invention thereis provided a method of treating type 2 diabetes, insulin resistance,syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia orobesity in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (1).

According to this further feature of this aspect of the invention thereis provided a method of treating type 2 diabetes in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (1).

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular cell-proliferation disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged.

In addition to their use in therapeutic medicine, the compounds offormula (1) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of cell cycle activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

Each Example is independently provided as a further aspect of theinvention.

EXAMPLES

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

-   (i) temperatures are given in degrees Celsius (° C.); operations    were carried out at room or ambient temperature, that is, at a    temperature in the range of 18-25° C. and under an atmosphere of an    inert gas such as argon;-   (ii) organic solutions were dried over anhydrous magnesium sulphate;    evaporation of solvent was carried out using a rotary evaporator    under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath    temperature of up to 60° C.;-   (iii) chromatography means flash chromatography on silica gel; thin    layer chromatography (TLC) was carried out on silica gel plates;    where a Bond Elut column is referred to, this means a column    containing 10 g or 20 g or 50 g of silica of 40 micron particle    size, the silica being contained in a 60 ml disposable syringe and    supported by a porous disc, obtained from Varian, Harbor City,    Calif., USA under the name “Mega Bond Elut SI”; “Mega Bond Elut” is    a trademark; where a Biotage cartridge is referred to this means a    cartridge containing KP-SIL™ silica, 60μ, particle size 32-63 mM,    supplied by Biotage, a division of Dyax Corp., 1500 Avon Street    Extended, Charlottesville, Va. 22902, USA;-   (iv) in general, the course of reactions was followed by TLC and    reaction times are given for illustration only;-   (v) yields are given for illustration only and are not necessarily    those which can be obtained by diligent process development;    preparations were repeated if more material was required;-   (vi) where given, NMR data is in the form of delta values for major    diagnostic protons, given in parts per million (ppm) relative to    tetramethylsilane (TMS) as an internal standard, determined at 300    MHz using perdeuterio dimethyl sulphoxide (DMSO-δ₆) as solvent    unless otherwise indicated, other solvents (where indicated in the    text) include deuterated chloroform CDCl₃;-   (vii) chemical symbols have their usual meanings; SI units and    symbols are used;-   (viii) reduced pressures are given as absolute pressures in Pascals    (Pa); elevated pressures are given as gauge pressures in bars;-   (ix) solvent ratios are given in volume: volume (v/v) terms;-   (x) mass spectra (MS) were run with an electron energy of 70    electron volts in the chemical ionisation (CI) mode using a direct    exposure probe; where indicated ionisation was effected by electron    impact (EI), fast atom bombardment (FAB) or electrospray (ESP);    values for m/z are given; generally, only ions which indicate the    parent mass are reported and unless otherwise stated the value    quoted is (M−H)⁻;-   (xi) The following abbreviations are used:    -   SM starting material;    -   EtOAc ethyl acetate;    -   MeOH methanol;    -   EtOH ethanol;    -   DCM dichloromethane;    -   HOBT 1-hydroxybenzotriazole;    -   DIPEA di-isopropylethylamine;    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide        hydrochloride;    -   Et₂O diethyl ether;    -   THF tetrahydrofuran;    -   DMF N,N-dimethylformamide;    -   HATU        O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate    -   DMAP 4-dimethylaminopyridine    -   TBAF tetrabutylammonium fluoride    -   TFA trifluoroacetic acid

Certain intermediates described hereinafter within the scope of theinvention may also possess useful activity, and are provided as afurther feature of the invention.

Example 12-Chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9; 5.07 g, 25.2mmol), HOBT (3.40 g, 25.2 mmol), anhydrous DMF (100 mL) and finally EDCI(4.82 g, 25.2 mmol) were added to methyl3-amino-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetate (Method 1; 5.89 g,25.2 mmol) and the reaction was stirred for 18 h. The reaction was thendiluted with water (200 mL) and stirred vigorously for 30 min. Theresultant precipitate was filtered and washed with water (50 mL), EtOAc(2×20 mL) and Et₂O (2×10 mL). The collected solid was further driedunder high vacuum for 6 h to furnish the title compound (8.00 g, 76%) asa pale yellow solid.

¹H NMR 3.15 (m, 2H), 3.64 (s, 3H), 4.74 (m, 3H), 7.18 (m, 6H), 8.58 (d,1H), 11.91 (s, 1H); MS m/z MH⁺ 418, 420.

Example 2N-[1-(Carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide

LiOH (1.41 g, 33.6 mmol) in H₂O (16.5 mL) was added to a stirringsolution of2-chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 1; 7.00 g, 16.8 mmol) in THF (88 mL) and the reaction wasstirred for 2 h. The reaction was quenched by addition of 1M aqueous HCl(200 mL) and EtOAc (400 mL) and the organic layer was dried (MgSO₄),filtered and evaporated. The resultant white foam was triturated withhot Et₂O (100 mL) cooled, filtered and dried to afford the titlecompound (6.00 g, 89%) as a white solid.

¹H NMR 3.14 (m, 2H), 4.52 (d, 1H), 4.75 (m, 2H), 7.03 (m, 3H), 7.18 (s,1H), 7.27 (m, 2H), 7.57 (d, 1H), 11.90 (s, 1H), 12.89 (br. s, 1H); MSm/z MH⁺ 404, 406.

Example 32-Chloro-N-[1-(carbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

Triethylamine (38 μL, 0.27 mmol) then ethyl chloroformate (26.1 μL, 0.27mmol) were added toN-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 2; 100 mg, 0.25 mmol) in anhydrous THF (2 mL) at 0° C. followedby stirring for 1 h. Concentrated aqueous NH₃ (1 mL) was added and thereaction was stirred for a further 1 h. Water (20 mL) and EtOAc (40 mL)were added and the organic layer was separated, washed with 1M HCl (20mL) and the organic layer was dried (MgSO₄), filtered and evaporated.The residue was purified by column chromatography (MeOH:DCM 1:19) toafford the title compound (56 mg, 56%) as a white solid.

¹H NMR 3.15 (m, 2H), 4.23 (d, 1H), 4.67 (d, 1H), 4.82 (m, 1H), 6.88 (d,1H), 7.05 (m, 2H), 7.14 (s, 2H), 7.24 (m, 2H), 7.54 (s, 1H), 8.51 (d,1H), 11.91 (s, 1H); MS m/z MH⁺ 403, 405.

Examples 4-7

The following examples were synthesised by an analogous method toExample 3:

Example 42-Chloro-N-[1-(N,N-dimethylcarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide Example 52-Chloro-N-[1-(N-methylcarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamideExample 62-Chloro-N-[1-(N-hydroxycarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamideExample 72-Chloro-N-{1-[N-(2-hydroxyethyl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

m/z Example NR¹R² ¹H NMR MH⁺ 4

2.84 (s, 3H), 3.03 (dd, 1H), 3.10 (s, 3H), 3.19 (app. t, 1H), 4.58 (d,1H), 4.74 (m, 1H), 4.93 (d, 1H), 6.87 (d, 1H), 7.03 (t, 1H), 7.09 (s,1H), 7.18 (s, 1H), 7.25 (m, 2H), 8.56 (d, 1H), 11.95 (s, 1H). 431, 433 5

2.60 (s, 3H), 3.05 (dd, 1H), 3.16 (app. t, 1H), 4.37 (d, 1H), 4.68 (d,1H), 4.87 (m, 1H), 6.88 (d, 1H), 7.04 (t, 1H), 7.10 (s, 1H), 7.18 (s,1H), 7.27 (m, 2H), 8.00 (m, 1H), 8.52 (d, 1H), 11.91 (s, 1H). 417, 419 6

3.02 (dd, 1H), 3.17 (app. t, 1H), 4.30 (d, 1H), 4.61 (d, 1H), 4.84 (m,1H), 6.92 (d, 1H), 7.05 (t, 1H), 7.09 (s, 1H), 7.27 (m, 2H), 8.52 (d,1H), 8.90 (s, 1H), 10.72 (s, 1H), 11.92 (s, 1H). 419, 421 7

3.04 (m, 1H), 3.10 (m, 3H), 3.39 (m, 2H), 4.32 (d, 1H), 4.73 (m, 3H),6.89 (d, 1H), 7.03 (t, 1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.27 (app. d,2H), 8.09 (t, 1H), 8.53 (d, 1H), 11.92 (s, 1H). 447, 449

Example 82-Chloro-N-[1-(2-hydroxyethyl)-2-oxo-1,213,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrol-5-ylcarboxamide

Triethylamine (0.76 mL, 5.47 mmol) then ethyl chloroformate (0.52 mL,5.47 mmol) were added toN-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 2; 2.0 g, 4.97 mmol) in anhydrous THF (40 mL) at 0° C. followedby stirring for 1 h. LiBH₄ (2.0 M in THF, 3.1 mL, 6.21 mmol) was addedslowly and the mixture stirred for a further 30 min. The reaction wascarefully quenched with 1M HCl (200 mL) and EtOAc (400 mL) and theorganic layer was further washed with sat. aqueous NaHCO₃ (100 mL),brine (100 mL), dried (MgSO₄), filtered and evaporated. The residue wastriturated with refluxing Et₂O (30 mL) and after cooling the solid wasfiltered and dried to afford the title compound (1.70 g, 88%) as a whitesolid.

¹H NMR 3.04 (m, 2H), 3.59 (m, 2H), 3.91 (m, 1H), 4.01 (m, 1H), 4.72 (m,1H), 4.83 (m, 1H), 7.18 (m, 6H), 8.48 (d, 1H), 11.90 (s, 1H); MS m/z MH⁺390, 392.

Example 92-Chloro-N-[1-(2,3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

6M Aqueous HCl (1.47 mL) was added toN-{1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Method 3; 340 mg, 7.45 mmol) in THF (14 mL) and the reaction wasstirred for 4 h. The reaction was quenched by addition of triethylamine(1.5 mL) then diluted with water (30 mL) and EtOAc (40 mL). The organiclayer was separated, dried (MgSO₄), filtered and evaporated. The residuewas triturated with hot Et₂O (10 mL) and after cooling was filtered anddried to afford the title compound (260 mg, 83%) as white solid.

¹H NMR 3.07 (m, 3H), 3.81 (m, 2H), 4.01 (m, 2H), 4.71 (m, 3H), 7.16 (m,6H), 8.45 (app. d, 1H), 11.91 (s, 1H); MS m/z MH⁺ 420, 422.

Example 102-Chloro-N-{1-[(2,2-dimethyl-1,3-dioxolan-4(S)-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

The title compound was prepared as described for Method 2 using[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl methanesulfonate (J. Med.Chem., 26, 1983 950-57), followed by the coupling procedure of Method 3.

¹H NMR 1.32 (s, 1.5H), 1.33 (s, 1.5H), 1.37 (s, 1.5H), 1.42 (s, 1.5H),2.88 (m, 1H), 3.63 (m, 1H), 3.78 (app. t, 1H), 3.90 (dd, 0.5H), 4.04(dd, 0.5H), 4.14 (m, 1H), 4.33 (m, 2H), 4.68 (m, 1H), 6.82 (m, 2H), 7.10(m, 1H), 7.27 (m, 4H), 10.94 (br. s, 1H); MS m/z MNa⁺ 482, 484.

Example 112-Chloro-N-[1-(2(S),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

The title compound was prepared (as a mixture of diastereoisomers) byacid hydrolysis as described for Example 9 starting with2-chloro-N-[1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 10).

¹H NMR 3.07 (m, 3H), 3.81 (m, 2H), 4.01 (m, 2H), 4.71 (m, 3H), 7.16 (m,6H), 8.45 (app. d, 1H), 11.91 (s, 1H); MS m/z MH⁺ 420, 422.

Purification of the product by HPLC afforded the two individualdiastereoisomers

-   2-chloro-N-[1-(2(S),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide,    and-   2-chloro-N-[1-(2(S),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide    as white solids (stereochemistry not assigned):    First Eluting:

¹H NMR 3.10 (m, 2H), 3.25 (m, 2H), 3.72 (m, 1H), 3.88 (dd, 1H), 4.03(dd, 1H), 4.58 (t, 1H), 4.69 (q, 1H), 4.78 (d, 1H), 7.04 (m, 2H), 7.16(s, 1H), 7.28 (m, 3H), 8.47 (d, 1H), 11.93 (s, 1H); MS m/z 420

Second Eluting:

¹H NMR 2.98 (dd, 1H), 3.12 (t, 1H), 3.38 (t, 2H), 3.80 (m, 2H), 3.99 (q,1H), 4.63 (t, 1H), 4.72 (m, 1H), 4.87 (d, 1H), 7.03 (t, 1H), 7.10 (s,1H), 7.17 (s, 1H), 7.26 (m, 2H), 7.36 (d, 1H), 8.50 (d, 1H), 11.95 (s,1H); MS m/z 420

Example 122-Chloro-N-[1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

The title compound was prepared as described for Method 2 using[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl methanesulfonate (J. Org.Chem, 64, 1999 6782-6790), followed by the coupling procedure of Method3.

¹H NMR 1.32 (s, 1.5H), 1.33 (s, 1.5H), 1.37 (s, 1.5H), 1.42 (s, 1.5H),2.88 (m, 1H), 3.63 (m, 1H), 3.78 (app. t, 1H), 3.90 (dd, 0.5H), 4.04(dd, 0.5H), 4.14 (m, 1H), 4.33 (m, 2H), 4.68 (m, 1H), 6.82 (m, 2H), 7.10(m, 1H), 7.27 (m, 4H), 10.94 (br. s, 1H); MS m/z MNa⁺ 482, 484.

Example 132-Chloro-N-[1-(2(R),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

The title compound was prepared by acid hydrolysis as described forExample 9 starting with2-chloro-N-[1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 12).

¹H NMR 3.07 (m, 3H), 3.81 (m, 2H), 4.01 (m, 2H), 4.71 (m, 3H), 7.16 (m,6H), 8.45 (app. d, 1H), 11.91 (s, 1H); MS m/z MH⁺ 420, 422.

Purification of the product by HPLC afforded the two individualdiastereoisomers

-   2-chloro-N-{(3R)-1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide,    and    02-chloro-N-{(3R)-1-[(2S)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide,    as white solids (stereochemistry not assigned).    First Eluting:

¹H NMR 3.10 (m, 2H), 3.25 (m, 2H), 3.72 (m, 1H), 3.88 (dd, 1H), 4.03(dd, 1H), 4.58 (t, 1H), 4.69 (q, 1H), 4.78 (d, 1H), 7.04 (m, 2H), 7.16(s, 1H), 7.28 (m, 3H), 8.47 (d, 1H), 11.93 (s, 1H); MS m/z 420

Second Eluting:

¹H NMR 2.98 (dd, 1H), 3.12 (t, 1H), 3.38 (t, 2H), 3.80 (m, 2H), 3.99 (q,1H), 4.63 (t, 1H), 4.72 (m, 1H), 4.87 (d, 1H), 7.03 (t, 1H), 7.10 (s,1H), 7.17 (s, 1H), 7.26 (m, 2H), 7.36 (d, 1H), 8.50 (d, 1H), 11.95 (s,1H); MS m/z 420, 422

Example 142-Chloro-N-{1-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

4-Dimethylaminopyridine (5 mg, 0.038 mmol) and 4-hydroxypiperidine (42mg, 0.41 mmol) were added to a suspension ofN-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 2; 150 mg, 0.38 mmol) and EDCI (79 mg, 0.41 mmol) in THF (0.5mL) under an inert atmosphere. DMF (0.5 mL) was added and the mixturestirred at ambient temperature for 18 h. After pouring into water (10mL) the resultant solid was filtered off and washed with 1M HCl aq. andwater. Chromatography on silica gel (eluent gradient of CH₂Cl₂ toMeOH:CH₂Cl₂ (1:9)) afforded the title compound (109 mg, 59%) as an offwhite solid.

¹H NMR (400 MHz) 1.20-1.52 (m, 2H), 1.65-1.90 (m, 2H), 3.05 (m, 2H),3.27(m, 2H), 3.80 (m, 3H), 4.64 (dd, 1H), 4.75 (m, 2H), 4.96 (dd, 1H),6.89 (d, 1H), 7.04 (t, 1H), 7.11 (s, 1H), 7.19 (s, 1H), 7.28 (t, 1H),8.54 (d, 1H), 11.93 (s, 1H); MS m/z MH⁺ 487,

Examples 15-17

The following examples were synthesised by an analogous method to

Example 14 Example 152-Chloro-N-{1-[N-(1,3-dihydroxyprop-2-yl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamideExample 162-Chloro-N-{1-[N-(2-Methoxyethyl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide Example 172-Chloro-N-(1-{2-[(3a,6a-cis)-2,2-dimethyltetrahydro-5H-[1.3]dioxolo[4,5-c]pyrrol-5-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide

Example NR¹R² ¹H NMR (400 MHz) m/z SM (amine) 15

3.05 (dd, 1H), 3.18 (dd, 1H), 3.42 (m, 4H), 3.73 (m, 1H), 4.40 (d, 1H),4.63 (m, 2H), 4.77 (m, 2H), 6.93 (d, 1H), 7.05 (t, 1H), 7.11 (s, 1H),7.19 (s, 1H), 7.28 (t, 1H), 7.88 (d, 1H), 8.55 (d, 1H), 11.94 (s, 1H).477, 479 commercial 16

3.05 (dd, 1H), 3.25 (m, 9H), 4.33 (d, 1H), 4.73 (d, 1H), 4.85 (m, 1H),6.90 (d, 1H), 7.06 (t, 1H), 7.11 (s, 1H), 7.19 (s, 1H), 7.29 (t, 1H),8.20 (t, 1H), 8.54 (d, 1H), 11.94 (s, 1H). 461, 463 commercial 17

1.28, 1.29, 1.39, 1.42 (4 × s, 6H), 3.05 (dd, 1H), 3.19 (m, 2H), 3.61(quintet, 1H), 3.74 (dd, 1H), 3.88 (dd, 1H), 4.59 (dd, 1H), 4.84 (m,4H), 6.89 (t, 1H), 7.05 (t, 1H), 7.11 (s, 1H), 7.19 (s, 1H), 7.24 (t,1H), 7.30 (d, 1H), 8.56 (d, 1H), 11.94 (s, 1H). 529, 531 Org. Lett., 3,2001 456-468

Example 182-Chloro-N-(1-{2-[(cis)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide

1M HCl aq. (0.46 mL, 0.46 mmol) was added to2-chloro-N-(1-{2-[(3a,6a-cis)-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 17; 200 mg, 0.38 mmol) in EtOH (6 mL) and heated to 70° C. for3 hrs. 2M HCl (1 mL) was added and the mixture heated to 70° C. for 18h. After cooling all volatiles were removed under reduced pressure.Chromatography on silica gel (eluent gradient of CH₂Cl₂ to THF) andwashing the resultant solid with Et₂O then hexane afforded the titlecompound (170 mg, 92%) as an off white solid.

¹H NMR (400 MHz) 3.05 (dd, 1H), 3.21 (m, 2H), 3.42 (m, 2H), 3.77 (dd,1H), 4.03 (m, 1H), 4.14 (m, 1H), 4.51 (dd, 1H), 4.77 (m, 2H), 4.92 (d,1H), 5.02 (d, 1H), 6.93 (d, 1H), 7.05 (t, 1H), 7.11 (s, 1H), 7.19 (s,1H), 7.28 (m, 2H), 8.55 (d, 1H), 11.94 (s, 1H); MS m/z MH⁺ 489, 491.

Example 19

There is no Example number 19.

Example 202-Chloro-N-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

1-Hydroxybenzotriazole (0.69 g, 0.51 mmol) was added to a solution of3-amino-1-[2-(dimethylamino)ethyl]-3,4-dihydroquinolin-2(1H)-one (Method10, 100 mg, 0.427 mmol) in DMF (3 mL) followed by2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9, 86 mg,0.42 mmol) and EDCI (0.98 g, 0.51 mmol). The reaction was diluted withEtOAc (40 mL) and sat. aqueous NaHCO₃ (20 mL) and the separated organiclayer was dried (MgSO₄), filtered and evaporated to dryness.Purification by column chromatography (MeOH:DCM 1:9) afforded the titlecompound (70 mg, 56%) as a yellow solid.

¹H NMR 2.70 (s, 6H), 3.20 (m, 4H), 4.22 (m, 2H), 4.73 (m, 1H), 7.20 (m,6H), 8.57 (d, 1H), 12.94 (s, 1H); MS m/z 417, 419

Example 212-Chloro-N-{1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

The procedure of Method 3 was followed, using3-amino-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-3,4-dihydroquinolin-2(1H)-one(Method 11) and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(Method 9), to give the title compound (83%) as a white solid.

¹H NMR (CDCl₃) 1.43 (s, 3H), 1.47 (s, 3H), 2.18 (m, 1H), 2.88 (m, 1H),3.69 (m, 3H), 3.98 (m, 3H), 4.32 (dd, 1H), 4.70 (m, 1H), 6.85 (m, 2H),7.10 (m, 1H), 7.28 (m, 4H), 10.50 (br, 1H); MS m/z 496, 498.

Example 222-Chloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[12,3-b]pyrrole-5-carboxamide

Acid catalysed hydrolysis of the acetonide group of Example 21 followingthe procedure described for Example 9 gave the title compound (90%) as awhite solid.

¹H NMR 1.90 (m, 1H), 3.06 (m, 4H), 3.38 (m, 1H), 3.46 (m, 1H), 3.83 (dd,1H), 4.04 (m, 1H), 4.38 (t, 1H), 4.48 (t, 1H), 4.68 (m, 1H), 7.07 (m,2H), 7.17 (s, 1H), 7.28 (m, 3H), 8.48 (d, 1H), 11.92 (s, 1H); MS m/z516, 518.

Example 232,3-Dichloro-N-{1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[332-b]pyrrole-5-carboxamide

The procedure of Method 3 was followed using3-amino-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-3,4-dihydroquinolin-2(1H)-one(Method 11) and 2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid(Method 8) to give the title compound (85%) as a white solid.

¹H NMR 1.39 (s, 3H), 1.47 (s, 3H), 2.00 (m, 1H), 3.20 (m, 2H), 3.74 (m,2H), 3.83 (m, 3H), 4.18 (dd, 1H), 4.72 (quin, 1H), 7.07 (m, 1H), 7.20(s, 1H), 7.30 (m, 3H), 8.57 (d, 1H), 12.52 (s, 1H); MS m/z (M−H)⁻ 506,508.

Example 242,3-Dichloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide

Acid catalysed hydrolysis of the acetonide of Example 23 in exactly thesame manner as for the synthesis of Example 9 formed the title compound(91%) as a white solid.

¹H NMR 1.90 (m, 1H), 3.10 (m, 2H), 3.29 (s, 1H), 3.37 (m, 2H), 3.51 (m,1H), 3.86 (dd, 1H), 4.08 (m, 1H), 4.38 (t, 1H), 4.51 (t, 1H), 4.72 (m,1H), 7.04 (t, 1H), 7.20 (s, 1H), 7.29 (m, 3H), 8.58 (d, 1H), 12.49 (s,1H); MS m/z 468

Example 252-Chloro-N-(1-{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide

In an similar manner to Example 3, using2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9) as thecarboxylic acid and 3-aminopropane-1,2-diol as the amine the titlecompound (47%) was prepared as a solid.

¹H NMR: 3.03 (m, 2H), 3.16 (d, 1H), 3.24 (t, 1H), 3.29 (m, 2H), 3.52 (m,1H), 4.37 (dd, 1H), 4.47 (t, 1H), 4.74 (m, 2H), 4.82 (m, 1H), 6.93 (d,1H), 7.07 (t, 1H), 7.12 (s, 1H), 7.20 (s, 1H), 7.28 (m, 2H), 8.07 (m,1H), 8.56 (d, 1H), 11.93 (s, 1H); m/z 477,

Example 262-Chloro-N-{1-[2-(methoxy)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

EDCI (225 mg, 1.17 mmol) was added to a suspension of5-carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9, 234 mg, 1.06 mmol)and 3-amino-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one (Method 12;215 mg, 1.06 mmol) in DCM (20 mL) and the reaction stirred for 18 hours.The reaction was evaporated and the residue was partitioned betweenDCM:MeOH (9:1) (100 mL) and water (25 mL). The organic layer was thenseparated, dried (MgSO₄), filtered and evaporated. The residue waspurified by column chromatography (DCM to DCM:MeOH (9:1)) to afford thetitle compound (180 mg, 42%) as a yellow solid.

¹H NMR (CDCl₃) 2.89 (app. t, 1H), 3.36 (s, 3H), 3.66 (m, 3H), 4.10 (dt,1H), 4.28 (dt, 1H), 6.83 (d, 1H), 7.11 (dd, 1H), 7.28 (m, 5H), 10.78(br. s, 1H); MS m/z (M+Na)+426, 428.

Example 272-Chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

EDCI (1.09 g, 5.65 mmol) was added to a suspension of5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9, 1.04 g, 5.13 mmol)and (3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (Method 13;1.29 g, 5.13 mmol) in DCM (30 mL) and the reaction stirred for 18 hours.The reaction was evaporated and the residue was partitioned betweenDCM:MeOH (9:1) (100 mL) and aqueous K₂CO₃ (25 mL). The organic layer wasthen separated, dried (MgSO₄), filtered and evaporated. The residue waspurified by column chromatography (DCM to DCM:MeOH (9:1)) to give abrown solid. The solid was triturated with refluxing Et₂O (25 mL) andthe solid filtered, washed with Et₂O (25 mL) then hexane (25 mL) toafford the title compound (414 mg, 21%) as a pale brown solid.

¹H NMR 3.08 (dd, 1H), 3.23 (app. t, 1H), 4.81 (m, 1H), 5.12 (s, 2H),7.10 (s, 1H), 7.15 (t, 1H), 7.21 (s, 1H), 7.28 (d, 1H), 7.39 (m, 2H),8.66 (d, 1H), 11.99 (br. s, 1H); MS m/z (M−H)⁻383, 385

Example 282-Chloro-N-[1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

N-Methylmorpholine (118 μL, 1.07 mmol) then ethyl chloroformate (103 μL,1.07 mmol) were added toN-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 2; 431 mg, 1.07 mmol) in anhydrous THF (10 mL) at 0° C. After20 minutes N′-hydroxyethanimidamide (119 mg, 1.61 mmol) was added andthe reaction stirred at ambient temperature for 3 days then at refluxfor 5 hours. After evaporation to dryness the residue was suspended in1,4-dioxane and refluxed for 18 hours. On cooling the mixture wasdiluted with EtOAc (100 mL) and washed with H₂O (25 mL). The aqueous wasextracted with DCM (3×50 mL) and the combined organics dried (MgSO₄),filtered and evaporated. The residue was purified by columnchromatography (DCM to DCM:MeOH (9:1)) to give a yellow solid which wasdissolved in MeOH:DCM (1:4) (100 mL) and shaken with macroporoussilicate-carbonate scavenger resin (300 mg). Filtration then evaporationgave the title compound (291 mg, 61%) as an off-white solid.

¹H NMR 2.35 (s, 3H), 3.14 (dd, 1H), 3.30 (app. t, 1H), 4.86 (m, 1H),5.43 (d, 1H), 5.56 (d, 1H), 7.19 (m, 4H), 7.36 (m, 2H), 8.67 (d, 1H),11.98 (br. s, 1H); MS m/z (M+Na)⁺ 442, 444

Example 292-Chloro-N-[2-oxo-1-(1H-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

Sodium azide (178 mg, 2.73 mmol) and triethylamine hydrochloride (356mg, 2.59 mmol) were added to2-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 27; 300 mg, 0.78 mmol) in 1-methyl-2-pyrrolidinone (7 mL) andthen heated at 150° C. for 3 hours. On cooling the mixture was dilutedwith EtOAc (100 mL) and washed with H₂O (50 mL). The aqueous layer wasacidified with citric acid and extracted with MeOH:DCM (1:19) and thecombined organics dried (MgSO₄), filtered and evaporated. The residuewas purified by applying the material to a 10 g Isolute NH₂ column inMeOH:DCM (1:9) (10 mL) and eluting with MeOH:DCM (1:9) (6×10 mL). Thecolumn was eluted with MeOH: 2M HCl in Et₂O:DCM (5:4:45) (6×10 mL) andthe relevant fractions evaporated to afford the title product (246 mg,74%) as pale pink powder.

¹H NMR 3.09 (dd, 1H), 3.26 (app. t, 1H), 4.90 (m, 1H), 5.31 (d, 1H),5.59 (d, 1H), 7.09 (m, 3H), 7.19 (s, 1H), 7.31 (m, 2H), 8.59 (d, 1H),11.95 (br. s, 1H); MS m/z 450,

Example 302-Chloro-N-(1-{2-[(methylsulphonyl)amino]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide

Methanesulphonamide (90 mg, 0.94 mmol), 4-(dimethylamino)pyridine (287mg, 2.35 mmol) and EDCI (225 mg, 1.17 mmol) were added to a suspensionofN-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 2; 315 mg, 0.78 mmol) in DCM (50 mL) and stirred for 2 days.The reaction was diluted with MeOH:DCM (1:19) (50 mL) and washed with 1MHCl(aq). (50 mL), the organic layer was separated, dried (MgSO₄),filtered and evaporated. The residue was purified by applying thematerial to a 10 g Isolute NH₂ column in MeOH:DCM (1:9) (10 mL) andeluted with MeOH:DCM (1:9) (6×10 mL) then MeOH: 2M HCl in Et₂O:DCM(5:4:45) (6×10 mL) and the relevant fractions evaporated to give a pinkgum which was triturated with refluxing Et₂O (25 mL) and after coolingthe title product (206 mg, 55%) was collected by filtration as pale pinkpowder.

¹H NMR 3.06 (dd, 1H), 3.22 (m, 1H), 4.45-4.87 (m, 6H), 7.00 (d, 1H),7.09 (m, 2H), 7.19 (s, 1H), 7.30 (m, 2H), 8.59 (d, 1H), 11.95 (br. s,1H), 12.17 (br. s, 1H); MS m/z (M+Na)⁺ 503, 505.

Example 31N-{1-[(2Z)-2-Amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide

Hydroxylamine hydrochloride (181 mg, 2.60 mmol) in MeOH (5 mL) was addedto a solution of NaOMe in MeOH (10.20 mL, 0.25M) under an inertatmosphere followed by2-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 27; 500 mg, 1.30 mmol) in THF (7 mL) then stirred for 18 hours.The mixture was diluted with EtOAc (100 mL) and washed with brine (25mL), dried (Na₂SO₄), filtered and evaporated to afford the title product(550 mg, 100%) as a pale brown solid.

¹H NMR 3.04 (dd, 1H), 3.19 (app. t, 1H), 4.30 (d, 1H), 4.76 (m, 1H),5.39 (br. s, 2H), 7.02 (d, 1H), 7.08 (s, 1H), 7.17 (s, 1H), 7.18 (d,1H), 7.25-7.33 (m, 2H), 8.56 (d, 1H), 9.17 (br. s, 1H), 11.95 (br. s,1H), 12.05 (br. s, 1H); MS m/z 418, 420.

Example 322-Chloro-N-{2-oxo-1-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl]-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

N-[1-((2Z)-2-Amino-2-{[(ethoxycarbonyl)oxy]imino}ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Method 14) was dissolved in 1,4-Dioxane and the solvent distilled offwith the oil bath temperature 140° C. This was repeated 4 times. Theresidual solid was triturated with refluxing Et₂O (10 mL) and aftercooling filtered, washed with Et₂O (10 mL) and hexane (10 mL) to givethe title product (184 mg, 87% (2 steps)) as a pale brown solid.

¹H NMR 3.04 (dd, 1H), 3.22 (app. t, 1H), 4.82 (m, 1H), 4.93 (d, 1H),5.18 (d, 1H), 7.06-7.20 (m, 4H), 7.26-7.35 (m, 2H), 8.54 (d, 1H), 11.92(br. s, 1H), 12.54 (br. s, 1H); MS m/z (M−H)⁻ 442, 444

Example 33N-{1-[(5-Amino-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide

1,4-Dioxane (5 mL),2-chloro-N-[1-(2-hydrazino-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide(Method 15; 300 mg, 0.72 mmol), cyanogen bromide (80 mg, 0.75 mmol) and1,4-dioxane (2 mL) were added to a solution of Na₂CO₃ (77 mg, 0.72 mmol)in H₂O (1.7 mL) and stirred for 18 hours. The mixture was diluted withEtOAc (50 mL) and THF (20 mL) and washed with H₂O (25 mL). The organicwas dried (Na₂SO₄), filtered and evaporated. The residue was purified byreverse phase column chromatography to give a brown solid. This wastriturated with refluxing Et₂O (25 mL), filtered, washed with Et₂O (25mL) then hexane (25 mL) to afford the title compound (63 mg, 20%) as abrown powder.

¹H NMR 2.94 (app. t, 1H), 3.31 (dd, 1H), 4.81 (m, 1H), 5.03 (d, 1H),5.39 (d, 1H), 6.99 (m, 3H), 7.25 (m, 2H), 7.34 (d, 1H), 7.66 (d, 1H),11.37 (br. s, 1H); MS m/z (M−H)⁻ 441, 443.

Example 342-Chloro-N-{1-[2-(methylthio)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

EDCI (915 mg, 4.77 mmol) was added to a suspension of5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (801 mg, 3.97 mmol),3-amino-1-[2-(methylthio)ethyl]-3,4-dihydroquinolin-2(1H)-one (Method16; 1.40 g, 3.97 mmol) and 1-hydroxybenzotriazole (537 mg, 3.97 mmol) inDCM (60 mL) and the reaction stirred for 18 hours. The reaction wasevaporated and the residue was partitioned between DCM (100 mL) andwater (25 mL). The organic layer was then separated, dried (MgSO₄),filtered and evaporated. The residue was purified by columnchromatography (DCM to DCM:EtOAc (9:1)) to afford the title compound(660 mg, 40%) as a white solid.

¹H NMR 2.13 (s, 3H), 2.69 (t, 2H), 3.02 (dd, 1H), 3.13 (app. t, 1H),4.13 (t, 2H), 4.70 (m, 1H), 7.06 (d, 1H), 7.11 (s, 1H), 7.19 (s, 1H),7.22 (d, 1H), 7.27-7.36 (m, 2H), 8.51 (d, 1H), 11.92 (br. s, 1H); MS m/z(M−H)⁻ 418, 420

Example 352-Chloro-N-{1-[2-(methylsulfinyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H—thieno[2,3-b]pyrrole-5-carboxamide and Example 362-Chloro-N-{1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

Oxone (701 mg, 1.14 mmol) in H₂O (12 mL) was added to2-chloro-N-{1-[2-(methylthio)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 34; 462 mg, 1.10 mmol) in MeOH (12 mL) and stirred for 18hours. The mixture was diluted with EtOAc (100 mL) washed with saturatedNaHCO₃ (20 mL), dried (Na₂SO₄), filtered and evaporated. The residue waspurified by column chromatography (DCM to DCM:THF (3:2) then DCM:MeOH(4:1)) to give 2 yellow solids. Each solid was triturated separatelywith refluxing Et₂O (25 mL) and filtered, washed with Et₂O (25 mL) thenhexane (25 mL) to afford the title compounds (Example 35, 104 mg, 22%and Example 36, 230 mg, 46%) as solids.

Example 35

¹H NMR 2.62 (s, 3H), 3.05 (m, 4H), 4.28 (m, 2H), 4.67-4.77 (m, 1H), 7.09(m, 2H), 7.19 (s, 1H), 7.31 (m, 3H), 8.52 (dd, 1H), 11.93 (br. s, 1H);MS m/z (M−H)⁻ 434, 436.

Example 36

¹H NMR 3.03 (dd, 1H), 3.09 (s, 3H), 3.16 (app. t, 1H), 3.38-3.52 (m,2H), 4.34 (t, 2H), 4.67-4.77 (m, 1H), 7.06-7.13 (m, 2H), 7.19 (s, 1H),7.22 (d, 1H), 7.24-7.37 (m, 3H), 8.52 (dd, 1H), 11.94 (br. s, 1H); MSm/z (M−H)⁻ 450, 452

Example 372,3-Dichloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide

5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 8; 595 mg, 2.52mmol), HOBt (340 mg, 2.52 mmol), DCM (100 mL) and finally EDCI (483 mg,2.52 mmol) were added to methyl(3-amino-2-oxo-3,4-dihydroquinolin-[(2H)-yl)acetate (Method 1, 590 mg,2.52 mmol) and the reaction was stirred for 18 hours The reaction wasthen diluted with water (50 mL) and stirred vigorously for 30 min. Theresultant precipitate was filtered and washed with Et₂O (2×20 mL). Afterfiltration the resultant solid was then triturated with refluxing Et₂O(25 mL) and after cooling the title compound (528 mg, 46%) was collectedagain by filtration as a white solid.

¹H NMR 3.10 (dd, 1H), 3.21 (app. t, 1H), 3.69 (s, 3H), 4.67 (d, 1H),4.81 (m, 2H), 7.07 (m, 2H), 7.23 (s, 1H), 7.31 (m, 2H), 8.69 (d, 1H),12.51 (s, 1H); MS m/z 452, 454.

Example 38N-[1-(Carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide

The title compound was prepared by the method described for Example 2using2,3-Dichloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide(Example 37) as starting material.

¹H NMR 3.15 (m, 2H), 4.54 (d, 1H), 4.78 (m, 2H), 7.06 (m, 2H), 7.21 (m,1H), 7.28 (m, 2H), 8.67 (d, 1H), 12.52 (s, 1H), 12.94 (br, 1H); MS m/z438, 440

Example 392,3-Dichloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide

The title compound was prepared by the method described for Example 8usingN-[1-(Carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide(Example 38) as starting material.

¹H NMR 3.10 (m, 2H), 3.61 (m, 2H), 3.98 (m, 2H), 4.79 (m, 2H), 7.05 (m,1H), 7.28 (m, 3H), 8.57 (d, 1H), 12.49 (s, 1H); MS m/z 424.

Example 402,3-Dichloro-N-{1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide

Acid catalysed hydrolysis of2,3-dichloro-N-{1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide(Method 7) following the procedure described for Example 9 gave thetitle compound (92%) as a white solid.

¹H NMR 3.06 (m, 2H), 3.33 (m, 2H), 3.85 (m, 3H), 4.70 (m, 3H), 7.04 (m,1H), 7.24 (m, 4H), 8.58 (2×d, 1H), 12.49 (s, 1H); MS m/z 454, 456

Example 412-Chloro-N-{1-[3-(dimethylamino)-2-hydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

The title compound was prepared by a two-step coupling-epoxide openingsequence. Standard amide bond formation analogous to Method 3 exceptusing 3-amino-1-(oxiran-2-ylmethyl)-3,4-dihydroquinolin-2(1H)-one(Method 19) as amine and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylicacid (Method 9) as the acid component formed the title compound as awhite solid which was used without further purification. The crude amideproduct (150 mg) was dissolved in EtOH (5 mL) followed by addition ofdimethylamine in EtOH (5.0-6.0 M in EtOH, 0.5 mL) and the reaction wasstirred overnight under argon. The reaction was diluted with EtOAc (40mL) and sat. aqueous NaHCO₃ (20 mL) and the separated organic layer wasdried (MgSO₄), filtered and evaporated to dryness. Purification bycolumn chromatography (MeOH:DCM 2:9) afforded the title compound (41 mg)as a yellow solid.

¹H NMR 1.85 (s, 3H), 2.16 (s, 3H), 2.27 (m, 2H), 3.05 (m, 2H), 3.20 (br,1H), 3.63 (m, 1H), 3.84 (m, 1H), 4.08 (m, 1H), 4.68 (m, 1H), 7.15 (m,6H), 8.48 (d, 1H), 12.00 (s, 1H); MS m/z 447

Example 422-Chloro-N-{2-oxo-1-[(2-oxo-1,3-dioxan-5-yl)methyl]-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

Carbonyl diimidazole (143 mg, 0.88 mmol) was added to2-chloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 22; 250 mg, 0.58 mmol) followed by DMAP (2 mg) and the reactionwas heated at 50° C. for 4 hours. The reaction was quenched by additionof EtOAc (50 mL) and H₂O (10 mL) and the organic layer was separated andwashed further with saturated aqueous NaHCO₃, 1M HCl (aq.) and brine.The organic layer was then dried (MgSO₄), filtered and evaporated.Trituration with hot Et₂O (15 mL), cooling and filtration afforded thetitle compound (182 mg, 0.40 mmol, 68%) as a white solid.

¹H NMR 3.07 (dd, 1H), 3.21 (t, 1H), 4.22 (m, 5H), 4.45 (m, 2H), 4.73 (m,1H), 7.07 (m, 2H), 7.18 (s, 1H), 7.21 (m, 3H), 8.50 (d, 1H), 11.95 (s,1H); MS m/z 460, 462.

Example 432-Chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

TBAF (1.0 M in THF, 4.92 mL, 4.92 mmol) was added toN-[1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Method 20, 1.84 g, 3.56 mmol) in THF (15 mL) and the reaction wasstirred for 48 hours. The reaction was quenched by the addition of EtOAc(50 mL) and NH₄Cl (aq.) (20 mL) and the organic layer was dried (MgSO₄),filtered and evaporated. Purification by column chromatography affordedthe title compound (1.24 g, 3.08 mmol, 86%) as a white solid.

¹H NMR 1.79 (m, 2H), 3.13 (m, 2H), 3.52 (m, 2H), 4.01 (m, 2H), 4.58 (m,2H), 4.73 (quin, 1H), 7.20 (m, 6H), 8.53 (d, 1H), 11.96 (s, 1H); MS m/z404

Example 442-Chloro-N-{1-[3-(methylamino)-3-oxopropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide

Pyridinium dichromate (329 mg, 0.88 mmol) was added to2-chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 43; 100 mg, 0.248 mmol) in DMF (3 mL) and the reaction wasstirred for 24 hours. The reaction was diluted with EtOAC (20 mL) andfiltered through celite. The filtrate was washed with 1M HCl (aq.) andthe organic layer was dried (MgSO₄), filtered and evaporated to affordthe crude acid which was used without purification. Standard amide bondformation analogous to Method 3 except using methylamine (2.0 M in THF)as amine gave the title compound (65 mg, 61% over 2 steps) as a whitesolid.

¹H NMR 2.43 (m, 2H), 2.60 (s, 3H), 3.08 (m, 2H), 4.12 (m, 2H), 4.70 (m,1H), 7.07 (m, 2H), 7.23 (m, 2H), 7.32 (m, 2H), 7.89 (s, 1H), 8.50 (d,1H), 11,92 (s, 1H); MS m/z 431

Example 452-Chloro-N-[2-oxo-1-(2-oxobutyl)-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

Standard amide bond formation analogous to Method 3 using3-amino-1-(2-oxobutyl)-3,4-dihydroquinolin-2(1H)-one (Method 22) asamine and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9)as the acid component formed the title compound (56%) as a white solid.

¹H NMR 0.95 (t, 3H), 2.58 (m, 2H), 3.04 (dd, 1H), 3.19 (t, 1H), 4.73 (m,2H), 4.94 (d, 1H), 6.88 (d, 1H), 7.05 (m, 2H), 7.24 (m, 3H), 8.52 (d,1H), 11.90 (s, 1H); MS m/z 416, 418

Example 462-Chloro-N-[1-(2-hydroxybutyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

Sodium borohydride (13.7 mg, 0.36 mmol) was added to a solution of2-chloro-N-[1-(2-hydroxybutyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 45, 100 mg, 0.24 mmol) in MeOH (10 mL) and the reaction wasstirred for 1 hour. The reaction was quenched by addition of H₂O (5 mL)and EtOAc (20 mL) and the organic layer was dried (MgSO₄), filtered andevaporated. The crude solid was triturated with Et₂O (5 mL) and theproduct (75 mg, 75%) was collected by filtration and isolated as a 2:1mixture of diastereomers.

¹H NMR 0.90 (m, 3H), 1.38 (m, 2H), 3.07 (m, 2H), 3.71 (m, 2H), 4.03 (m,1H), 4.75 (m, 2H), 7.04 (t, 1H), 7.13 (s, 1H), 7.19 (s, 1H), 7.34 (m,3H), 8.48 (d, 1H), 11.95 (s, 1H); MS m/z 418

Example 472,3-Dichloro-N-[(6S)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-6-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide

TFA (2 mL) was added to a solution of(6S)-6-(tritylamino)-5,6-dihydroimidazo[1,2-a]pyrimidin-7(8H)-one(Method 23, 400 mg, 1 mmol) in DCM (20 mL) and the reaction was stirredat ambient temperature for 1 hours The volatiles were removed byevaporation under reduced pressure to afford(6S)-6-amino-5,6-dihydroimidazo[1,2-a]pyrimidin-7(8H)-one which was usedcrude in the next stage. HOBT (135 mg, 1 mmol) was added to a solutionof 2,3-dichloro-4H— thieno[3,2-b]pyrrol-5-yl-2-carboxylic acid (Method8; 236 mg, 1 mmol) and DIPEA (0.52 mL, 3 mmol) and the reaction stirredat ambient temperature for 5 mins. EDCI (210 mg, 1.1 mmol) was thenadded and the reaction stirred at ambient temperature for a further 16hours The reaction mixture was filtered to afford a yellow solid, whichwas washed with methanol to afford the title compound as a pale yellowsolid (202 mg, 55%).

¹H NMR 3.97 (t, 1H), 4.35 (dd, 1H), 4.92 (m, 1H), 6.66 (s, 1H), 6.88 (s,1H), 7.17 (s, 1H), 8.64 (d, 1H), 11.21 (br s, 1H), 12.51 (br s, 1H); MSm/z 370.

Example 482,3-Dichloro-N-(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide

Triethylamine (404 mg, 4 mmol), HOBT (148.5 mg, 1.1 mmol),2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (Method 8, 234mg, 1.0 mmol) and 3-amino-3,4-dihydro-1,5-naphthyridin-2(1H)-onedihydrochloride (Method 25, 234 mg, 1.0 mmol) were dissolved indimethylformamide (20 mL.). EDCI (210 mg, 1.1 mmol.) was then added andthe reaction mixture stirred at ambient temperature for 2 hours. Thereaction mixture was concentrated to small volume and diluted with water(50 mL). The resulting precipitate was collected by filtration, washedwith methanol (2×10 mL) and ether and dried under vacuum at 50° C. togive the title compound. (237 mg, 71%)

¹H NMR 3.1-3.4 (m, 2H); 4.85 (m, 1H); 7.2 (m, 3H); 8.1 (d, 1H); 8.6 (d,1H); 10.44 (s, 1H); 12.48 (s, 1H); MS m/z 379.

Example 492-Chloro-N-(2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide

DIPEA (297 mg, 2.3 mmol), HOBT (128 mg, 0.95 mmol),2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9, 154 mg.,0.767 mmol) and 3-amino-3,4-dihydro-1,7-naphthyridin-2(1H)-one (Method28,300 mg, 0.767 mmol) were suspended in DCM (10 mL). EDCI (183 mg, 0.95mmol) was then added and the reaction mixture stirred at ambienttemperature for 2 hrs. The reaction mixture was filtered and thefiltrate was diluted with ethyl acetate (100 mL), washed with saturatedaqueous sodium bicarbonate (2×25 mL) and brine (25 mL), dried (MgSO₄)and evaporated under reduced pressure to give a light brown solid whichwas washed with methanol (20 mL) and dried to give the title compound(45 mg, 17%).

Example 50N-(6-Fluoro-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide

Et₃N (184 μL, 1.32 mmol), HOBT (89 mg, 0.66 mmol),3-amino-6-fluoro-3,4-dihydro-2(1H)-quinolinone monohydrochloride (CASReg. No: 82420-54-0) (143 mg, 0.66 mmol), and EDAC (127 mg, 0.66 mmol)were added to a solution of2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (133 mg, 0.66 mmol)in anhydrous DMF (3.5 mL). The reaction was stirred at ambienttemperature for approximately 16 h, and then poured into water (50 mL).This was stirred vigorously for about 10 mins. and filtered. Thecollected precipitate was washed with water and dried in vacuum at 40°C., to give the title compound (203 mg, 84%) as an amorphous solid.

¹H NMR 3.12 (m, 2H), 4.71 (m, 1H), 6.89 (m, 1H), 7.02 (m, 1H), 7.07 (m,1H), 7.10 (s.1H), 7.13 (dd, 1H), 7.20 (s, 1H), 7.48 (d, 1H), 10.37 (s,1H), 11.95 (s, 1H); MS m/z 364, 366.

Example 51N-(6-Methoxy-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide

This example was made by the process of Example 50, using3-amino-3,4-dihydro-6-methoxy-2(1H)-quinolinone monohydrochloride (CASReg No: 35287-38-8) and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylicacid (Method 9).

¹H NMR 3.03 (dd, 1H), 3.09 (t, 1H), 3.72 (s, 3H), 4.68 (m, 1H), 6.82 (m,3H), 7.09 (s, 1H), 7.20 (s, 1H), 8.43 (d, 1H), 10.20 (s, 1H), 11.92 (s,1H); MS m/z 376,378.

Methods

Method 1

Methyl(3-amino-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetate

Sodium hydride (60% in oil, 2.52 g, 63.0 mmol) was added to3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28,1985, 1511-16; 5.0 g, 25.2 mmol), in anhydrous DMF (100 mL) at 0° C.over a period of 5 min keeping the internal temperature at <10° C. Thereaction was stirred for a further 30 min before addition of methylbromoacetate (2.85 mL, 30.2 mmol), then stirred for a further 60 min.The reaction was quenched by addition of 1M aqueous HCl (5 mL) and thevolatiles were removed by evaporation. The residue was dissolved in DCM(250 mL) and washed with sat. aqueous NaHCO₃ (100 mL) and the organiclayer was dried (MgSO₄), filtered and evaporated to yield the titlecompound (5.89 g, 25.2 mmol) as yellow paste which was used withoutfurther purification.

¹H NMR 2.21 (br. s, 2H), 2.78 (d, 1H), 2.97 (dd, 1H), 3.47 (dd, 1H),3.67 (s, 3H), 4.55 (d, 1H), 4.78 (d, 1H), 6.96 (m, 2H), 7.23 (m, 2H); MSm/z MH⁺ 235.

Method 2

3-Amino-1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one

Sodium hydride (60% in oil, 191 mg, 4.70 mmol) was added to3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28,1985; 1511-16,450 mg, 2.27 mmol), in anhydrous DMF (6 mL) at 0° C. overa period of 5 min keeping the internal temperature at <10° C. Thereaction was stirred for a further 30 min before addition of(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (J. Med. Chem.35, 1992, 1650-62; 528 mg, 2.50 mmol) and the reaction has then heatedto 80° C. for a period of 5 h. The reaction was then cooled andevaporated before addition of sat. aqueous NaHCO₃ (20 mL) and EtOAc (50mL). The organic layer was then dried (MgSO₄), filtered and evaporatedand the residue was purified by column chromatography (MeOH:DCM 1:19) toafford the title compound (330 mg, 53%) as colourless oil.

¹H NMR 1.33 (s, 3H), 1.40 (s, 1.5H), 1.45 (s, 1.5H), 1.96 (br. s, 2H),2.89 (m, 1H), 3.07 (m, 1H), 3.60 (m, 1H), 3.82 (m 1.5H), 4.08 (m, 1.5H),4.33 (m, 2H), 7.04 (m, 1H), 7.23 (m, 3H); MS m/z MH⁺ 277.

Method 3

N-1-(2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide)

5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9; 243 mg, 1.20mmol), HOBT (178 mg, 1.32 mmol), anhydrous DMF (10 mL) and finally EDCI(252 mg, 1.32 mmol) were added to3-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3,4-dihydroquinolin-2(1H)-one(Method 2, 330 mg, 1.20 mmol) and the reaction was stirred for 18 h. Thereaction was evaporated and the residue was dissolved in EtOAc (100 mL)and washed with 1M aqueous HCl (50 mL) and the organic layer was furtherwashed with sat. aqueous NaHCO₃ (30 mL) and brine (30 mL). The organiclayer was then separated, dried (MgSO₄), filtered and evaporated. Theresidue was purified by column chromatography (EtOAc:hexanes 1:2) toafford the title compound (382 mg, 69%) as a white solid.

¹H NMR 1.32 (s, 1.5H), 1.33 (s, 1.5H), 1.37 (s, 1.5H), 1.42 (s, 1.5H),2.88 (m, 1H), 3.63 (m, 1H), 3.78 (app. t, 1H), 3.90 (dd, 0.5H), 4.04(dd, 0.5H), 4.14 (m, 1H), 4.33 (m, 2H), 4.68 (m, 1H), 6.82 (m, 2H), 7.10(m, 1H), 7.27 (m, 4H), 10.94 (br. s, 1H); MS m/z MNa⁺ 482, 484.

Method 4

3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole

Methanolic sodium methoxide solution (28%) (5 ml, 25.9 mmol) was dilutedwith MeOH (5 ml) and was cooled to −25° C. under nitrogen. A solution of4-chloro-2-thienylcarboxaldehyde (J Heterocyclic Chem, 1976, 13, 393;1.1 g, 7.5 mmol) and methyl azidoacetate (3.0 g, 26.1 mmol) in MeOH (20ml) was added dropwise, maintaining the temperature at −25° C. Oncompletion of addition the solution was allowed to warm to 5° C. over aperiod of approximately 16 hours. The solution was added to saturatedaqueous ammonium chloride (250 ml) and the mixture was extracted usingDCM. The combined organic layers were concentrated at 0° C. The residuewas taken up in xylene (30 ml) and this solution was added dropwise toxylene (120 ml) under reflux. The solution was heated under reflux for30 minutes before being cooled and concentrated. The title compound waspurified by a mixture of crystallisation (EtOAc/isohexane) andchromatography on a Bond Elut column eluting with a graduated solvent of5-50% EtOAc in isohexane (640 mg, 40%). NMR (CDCl₃) 9.1 (1H, br), 7.1(2H, s), 3.9 (3H, s); m/z 214.3.

Methods 5 and 6

The following compounds were made by the process of Method 4 using theappropriate starting materials Meth Compound NMR (CDCl₃) M/z 5¹

9.2 (1H, br), 7.0 (1H, s), 3.9 (3H, s) 248.2 6²

9.4-9.2 (1H, br), 7.0 (1H, s), 6.9 (1H, s), 3.9 (3H, s) 214¹Aldehyde: DE 2814798²Aldehyde: Gronowitz et al. Tetrahedron Vol. 32 1976 p. 1403Method 7

5-Carboxy-3-chloro-4H-thieno[3,2-b]pyrrole

3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole (Method 4; 0.61 g,2.83 mmol) was taken up in MeOH (10 ml) and was heated under reflux.Aqueous lithium hydroxide (2.0 M, 3.0 ml, 6.0 mmol) was addedportionwise over 45 minutes. The mixture was heated under reflux for 30minutes before being cooled and concentrated. Water (20 ml) was addedand the solution was neutralised using aqueous hydrochloric acid (2.0 M,3.0 ml). The solution was extracted using EtOAc, and the combinedorganic layers were concentrated to afford the title compound as ayellow solid (0.57 g, 100%). NMR: 12.4 (1H, br), 7.4 (1H, s), 7.0 (1H,s); m/z 200.3.

Methods 8 and 9

The following compounds were made by the process of Method 7 using theappropriate starting materials. Method Compound NMR M/z SM 8

7.0 (1H, s) 234.2 Method 5 9

12.6-12.7 (1H, b), 12.0-12.1 (1H, b), 7.15 (1H, s), 6.9 (1H, s) 183Method 6Method 10

3-Amino-1-[2-(dimethylamino)ethyl]-3,4-dihydroquinolin-2(1H)-one

Sodium hydride (60% in oil, 70.5 mg, 1.75 mmol) was added to3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (100 mg, 0.50 mmol),in anhydrous DMF (2 mL) at 0° C. over a period of 5 min. The reactionwas stirred for a further 30 min before addition of2-(dimethylaminoethyl) chloride hydrochloride (80 mg, 0.55 mmol) and thereaction has then heated to 80° C. for a period of 5 hours The reactionwas then cooled and evaporated before addition of sat. aqueous NaHCO₃(20 mL) and EtOAc (50 mL). The organic layer was then dried (MgSO₄),filtered and evaporated and the residue was used without furtherpurification.

¹H NMR 1.25 (s, 2H), 2.35 (s, 6H), 2.56 (m, 2H), 2.81 (d, 1H), 3.05 (dd,1H), 3.56 (dd, 1H), 4.08 (m, 2H), 7.15 (m, 4H); MS m/z 234

Method 11

3-Amino-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-3,4-dihydroquinolin-2(1H)-one

The title compound was prepared in an analogous method to Method 10using (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate [CASregistary number 131372-64-0] as elecrophile.

¹H NMR 1.41 (s, 3H), 1.47 (s, 3H), 1.74 (s, 2H), 2.21 (m, 1H), 2.82 (d,1H), 3.06 (dd, 1H), 3.57 (dd, 1H), 3.73 (m, 2H), 3.93 (m, 3H), 4.15 (m,1H), 7.02 (t, 1H), 7.19 (m, 2H), 7.26 (m, 1H); MS m/z 291

Method 12

3-Amino-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one

Sodium hydride (60% in oil, 321 mg, 8.03 mmol) was added to3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28,1985; 1511-16; 759 mg, 3.82 mmol) in anhydrous DMF (10 mL) at 0° C. overa period of 5 min. After 1 hour 2-bromoethyl methyl ether (0.40 mL, 4.20mmol) was added and stirring maintained for 18 hours. The reaction wasdiluted with EtOAc (100 mL) and washed with sat. aqueous K₂CO₃ (20 mL).The aqueous was extracted with DCM (3×50 mL) and the combined organicsdried (Na₂SO₄), filtered and evaporated. The residue was purified bycolumn chromatography (DCM to DCM:MeOH (4:1)) to afford the titlecompound (654 mg, 78%) as a brown oil.

¹H NMR (CDCl₃) 1.82 (br. s, 2H), 2.85 (app. t, 1H), 3.06 (dd, 1H), 3.36(s, 3H), 3.61 (m, 3H), 4.02 (dt, 1H), 4.24 (dt, 1H), 7.02 (dt, 1H), 7.19(m, 2H), 7.27 (t, 1H).

Method 13

3-Amino-1-(2-cyanomethyl)-3,4-dihydroquinolin-2(1H)-one

Sodium hydride (60% in oil, 2.74 g, 68.5 mmol) was added to3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28,1985; 1511-16, 6.47 g, 32.6 mmol) in anhydrous DMF (70 mL) at 0° C. overa period of 5 min. After 1 hour the mixture was warmed to ambienttemperature, stirred for 2 hours then cooled in an ice bath beforebromoacetonitrile (2.28 mL, 32.68 mmol) was added. The mixture was againwarmed to ambient temperature and stirred for 18 hours. The reaction wasdiluted with EtOAc (100 mL) and washed with sat. aqueous K₂CO₃ (20 mL).The aqueous was extracted with DCM:MeOH (19:1) (3×50 mL) and thecombined organics dried (Na₂SO₄), filtered and evaporated. The residuewas purified by column chromatography (DCM to DCM:MeOH (9:1)) to affordthe title compound (5.28 g, 81%) as a brown oil.

¹H NMR (CDCl₃) 1.79 (br. s, 2H), 2.90 (app. t, 1H), 3.11 (dd, 1H), 3.65(dd, 1H), 4.68 (d, 1H), 5.03 (d, 1H), 7.05 (d, 1H), 7.13 (t, 1H), 7.25(d, 1H), 7.35 (t, 1H); MS m/z 202.

Method 14

N-[1-((2Z)-2-Amino-2-{[(ethoxycarbonyl)oxy]imino}ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide

Ethyl chloroformate (60 μL, 0.63 mmol) was added to a suspension ofN-{1-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide(Example 31; 200 mg, 0.48 mmol) in dry pyridine (1 mL) under an inertatmosphere then stirred heated to 100° C. for 30 minutes. On cooling THF(10 mL) and added followed by EtOAc (50 mL) and 1M HCl aq. (20 mL). Theorganic was separated and dried (Na₂SO₄), filtered and evaporated togive a clear orange oil. This was used in the next stage withoutcharacterization or purification.

Method 15

2-Chloro-N-[1-(2-hydrazino-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide

Hydrazine monohydrate (1 mL, 20.6 mmol) was added to a suspension ofmethyl[3-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate(Example 1); 221 mg, 0.53 mmol) in EtOH (10 mL) and heated to reflux for20 hours. On cooling the mixture was concentrated under reduced pressureand H₂O (20 mL) added and the white precipitate filtered off and driedin vacuo to give the title product (169 mg, 76%) as an off white solid.

¹H NMR 3.04 (dd, 1H), 3.18 (app. t, 1H), 4.25 (br. s, 2H), 4.33 (d, 1H),4.69 (d, 1H), 4.88 (m, 1H), 6.93 (d, 1H), 7.06 (t, 1H), 7.11 (s, 1H),7.19 (s, 1H), 7.28 (m, 2H), 7.32 (m, 2H), 8.52 (d, 1H), 9.29 (br. s,1H), 11.67 (br. s, 1H); MS m/z 418, 420.

Method 16

3-Amino-1-[2-(methylthio)ethyl]-3,4-dihydroquinolin-2(1H)-one

Prepared by an analogous method to3-amino-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one (Method 12)using 2-chloroethyl methyl sulphide instead of 2-bromoethyl methyl etherto give the title product as a clear, brown gum.

¹H NMR 2.13 (s, 3H), 2.66 (t, 2H), 2.73 (app. t, 1H), 2.96 (dd, 1H),3.44 (dd, 1H), 4.09 (t, 2H), 7.01 (t, 1H), 7.14 (d, 1H), 7.23 (m, 2H).

Method 17

2,3-Dichloro-N-{1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide

Standard amide bond formation analogous to Method 3 except using3-amino-1-[(2R)-2,3-dihydroxypropyl]-3,4-dihydroquinolin-2(1H)-one(Method 18) as amine and2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid as the acidcomponent formed the title compound as a white solid.

¹H NMR 1.23 (s, 3H), 1.30 (s, 3H), 3.12 (m, 2H), 3.71 (m, 1H), 4.15 (m,4H), 4.72 (m, 1H), 7.05 (t, 1H), 7.20 (s, 1H), 7.31 (m, 3H), 8.60 (d,1H), 12.49 (s, 1H); MS m/z

Method 18

3-amino-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,4-dihydroquinolin-2(1H)-one

Prepared according to Method 2 using[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl methanesulfonate (J. Org.Chem, 64, 1999 6782-6790) to give the title compound as a pale yellowoil.

¹H NMR (CDCl₃) 1.42 (m, 6H), 2.99 (m, 2H), 3.60 (m, 1H), 3.83 (m, 1.5H),4.11 (m, 1.5H), 4.38 (m, 2H), 7.03 (m, 1H), 7.26 (d, 3H).

Method 19

3-Amino-1-(oxiran-2-ylmethyl)-3,4-dihydroquinolin-2(1H)-one

The title compound was prepared in an analogous method to Method 1 usingglycidyl tosylate as elecrophile.

¹H NMR 2.70 (m, 1.5H), 3.25 (m, 4H), 4.12 (dd, 0.5H), 4.32 (dd, 0.5H),4.70 (dd, 0.5H), 7.20 (m, 4H); MS m/z 219

Method 20

N-[1-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide

Standard amide bond formation analogous to Method 3 except using3-amino-1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3,4-dihydroquinolin-2(1H)-one(Method 21) as amine and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylicacidas the acid component formed the title compound as a white solid.

¹H NMR 0.00 (s, 6H), 0.87 (s, 9H), 1.85 (m, 2H), 2.79 (t, 1H), 3.60 (m,3H), 4.05 (m, 2H), 4.56 (m, 1H), 6.77 (s, 1H), 6.82 (s, 1H), 7.02 (t,1H), 7.20 (m, 4H), 10.47 (s, 1H); MS m/z 518

Method 21

3-Amino-1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3,4-dihydroquinolin-2(1H)-one

The title compound was prepared in an analogous method to Method 1 using(3-bromopropoxy)(tert-butyl)dimethylsilane as electrophile.

¹H NMR 0.00 (s, 6H), 0.88 (s, 9H), 1.75 (s, 2H), 1.83 (m, 2H), 2.74 (d,1H), 3.00 (dd, 1H), 3.48 (dd, 1H), 3.66 (m, 2H), 3.98 (m, 2H), 6.96 (t,1H), 7.16 (m, 3H); MS m/z

Method 22

3-Amino-1-(2-oxobutyl)-3,4-dihydroquinolin-2(1H)-one

The title compound was prepared in an analogous method to Method 1 using1-bromo-2-butanone as electrophile.

¹H NMR 1.14 (t, 1H), 1.84 (br, 2H), 2.55 (q, 2H), 2.93 (m, 1H), 3.12(dd, 1H), 3.67 (dd, 1H), 4.49 (d, 1H), 4.92 (d, 1H), 6.61 (d, 1H), 7.03(t, 1H), 7.20 (t, 2H); MS m/z

Method 23

(6S)-6-(Tritylamino)-5,6-dihydroimidazo[1,2-a]pyrimidin-7(8H)-one

10% Pd/C (260 mg) was added to a solution of methyl3-(2-nitro-1H-imidazol-1-yl)-N-trityl-L-alaninate (Method 24, 1.2 g, 2.6mmol) in EtOH (100 mL) and the reaction stirred under an atmosphere ofhydrogen for 2 hours The reaction was filtered through celite and thefiltrate heated at reflux for approximately 2 hours Upon cooling thevolatiles were removed by evaporation under reduced pressure to affordthe title compound (1.04 g, 100%) as a white solid.

¹H NMR 2.63 (dd, 1H), 3.30 (t, 1H), 3.58 (dd, 1H), 4.13 (s, 1H), 6.20(d, 1H), 6.72 (d, 1H), 7.23 (m, 9H), 7.35 (m, 6H); MS m/z 395.

Method 24

Methyl 3-(2-nitro-1H-imidazol-1-yl)-N-trityl-L-alaninate

Di-isopropylazodicarboxylate (1.3 mL, 6.6 mmol) was added dropwise to asolution of 2-nitroimidazole (1.0 g, 9 mmol), N-trityl-L-serine methylester (2.0 g, 6 mmol) and triphenylphosphine (1.73 g, 6.6 mmol) in THF(100 mL). The reaction was stirred at ambient temperature forapproximately 5 hours The volatiles were removed by evaporation underreduced pressure and the residue purified by column chromatography(EtOAc:isohexane 1:19) to afford the title compound (1.2 g, 44%) as awhite solid.

¹H NMR 3.08 (s, 3H), 3.16 (d, 1H), 3.69 (m, 1H), 4.46 (dd, 1H), 4.62(dd, 1H), 7.15 (m, 15H), 7.33 (s, 1H), 7.93 (s, 1H); MS m/Z (M+NH₄)⁺479.

Method 25

3-Amino-3,4-dihydro-1,5-naphthyridin-2(1H)-one dihydrochloride

tert-Butyl(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-yl)carbamate(Method 26, 263 mg, 1 mmol) was dissolved in DCM (10 mL) and treatedwith 4M HCl in dioxan (10 mL). After stirring at ambient temperature for30 mins. the reaction mixture was evaporated under reduced pressure andthe residue triturated with ether (20 mL), to give a white solid whichwas collected by filtration, washed with ether and dried. (234 mg,100%).

¹H NMR 3.4 (m, 1H); 3.4 (m, 1H); 4.5 (m, 1H); 7.5 (m, 2H); 8.3 (d, 1H);8.75 (bs, 3H); 11.18(s, 1H) MS m/z 164

Method 26

tert-Butyl(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-yl)carbamate

Methyl 2-[(tert-butoxycarbonyl)amino]-3-(3nitropyridin-2-yl)acrylate(4:1 mixture of Z/E isomers) (Method 27, 1.1 g, 3.4 mmol) was dissolvedin ethanol and 10% palladium on carbon catalyst (250 mg) was added. Themixture was stirred under 1 atmosphere of hydrogen at ambienttemperature for 12 hours. After removing the catalyst by filtrationthrough Celite, the filtrate was concentrated under reduced pressure togive a yellow oil. The oil was dissolved in methanol (20 mL) and treatedwith a 0.5M solution of sodium methoxide in methanol (8 mL). Afterstirring at ambient temperature for 4 hrs. the mixture was diluted withwater (100 mL) and extracted with ethyl acetate (2×50 mL). The combinedextracts were washed with water (2×50 mL) and brine (50 mL), dried(MgSO₄) and evaporated under reduced pressure to give a white solid (528mg, 59%)

¹H NMR 1.4 (s, 9H); 3.1 (m, 2H); 4.3 (m, 1H); 7.0 (bd, 1H); 7.2 (m, 2H);8.1 (t, 1H); 10.26 (s, 1H); MS m/z 208.

Method 27

Methyl 2-[(tert-butoxycarbonyl)amino]-3-(3nitropyridin-2-yl)acrylate

Methyl[(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (1.33 g,4.46 mmol) was dissolved in dry THF (20 mL) and cooled to −78° C. undernitrogen. Tetramethylguanidine (490 mg, 4.26 mmol) was added and thesolution stirred at −78° C. for a further 10 mins. A solution of3-nitropyridine-2-carbaldehyde (Tetrahedron vol 0.54 (1998) p 6311) (618mg, 4.06 mmol) in dry THF (5 mL.) was added drop wise. After stirringthe solution for 2 hours. at −78° C. (50 mL) it was diluted with water(150 mL) and extracted with ethyl acetate. The combined extracts werewashed with water (2×20 mL) and brine (20 mL), dried (MgSO₄) andevaporated under reduced pressure to give a yellow oil, which waspurified by column chromatography (DCM) to give the title compound as a4:1 mixture of Z/E isomers (1.1 g, 84%).

¹H NMR 1.4 (s, 11.25H); 3.6 (s, 0.75H); 3.8 (s,3H); 6.7 (s, 1H); 6.9 (s,0.25H); 7.45 (m, 0.25H), 7.6 (m, 1H); 8.37 (d, 0.25H); 8.5 (d, 1H); 8.7(d, 0.25H); 8.9 (d, 1H); 9.8 (s, 0.25H); 10.3 (s, 1H); MS m/z 322

Method 28

3-Amino-3,4-dihydro-1,7-naphthfridin-2(1H)-one

tert-Butyl(2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridine-3-yl)carbamate(Method 29, 284 mg) was dissolved in DCM (10 mL) and treated withtrifluoroacetic acid (5 mL). After stirring at ambient temperature for 1hour the reaction mixture was evaporated under reduced pressure and theresidue triturated with ether (20 mL), to give a light brown solid whichwas collected by filtration, washed with ether and dried to give thetitle compound (346 mg, 82%) as a bis trifluroacetate salt.

¹H NMR 3.2 (m, 2H); 4.3 (m, 1H), 7.4 (d, 1H); 8.2 (s, 1H); 8.25 (d, 1H);8.6 (b, 3H); 11.0 (s, 1H)

Method 29

tert-Butyl(2-oxo-1,2,3,4-tetrahydro-1,7-naiphthyridine-3-yl)carbamate

Methyl 2-[(tert-butoxycarbonyl)amino]-3-(3nitropyridin-4-yl)acrylate(10:1 mixture of Z/E isomers) (Method 30, 1.57 g, 4.83 mmol) wasdissolved in ethanol and 10% palladium on carbon catalyst (250 mg) wasadded. The mixture was stirred under 1 atmosphere of hydrogen at ambienttemperature for 6 hours. After removing the catalyst by filtrationthrough Celite the filtrate was concentrated under reduced pressure togive a yellow oil which was purified by column chromatography (EluentDCM/MeOH gradient 0-10%) to give the title compound (284 mg, 22%).

¹H NMR 1.4 (s, 9H); 3.0 (m, 2H); 4.2 (m, 1H); 7.0 (d, 1H); 7.2 (d,1H);8.1 (m, 2H); 10.36 (s, 1H); MS m/z 264.

Method 30

Methyl-2-[(tert-butoxycarbonyl)amino]-3-(3nitropyridin-4-yl)acrylate

Methyl[(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (1.73 g,5.82 mmol) was dissolved in dry THF (20 mL) and cooled to −78° C. undernitrogen. Tetramethylguanidine (638 mg., 5.55 mmol) was added and thesolution stirred at −78° C. for a further 10 mins. A solution of3-nitroisonicotinaldehyde (Method 31, 804 mg, 5.29 mmol) in dry THF (5mL) was added dropwise. The resulting deep red solution was stirred for2 hrs. at −78° C., then poured into a mixture of ethyl acetate (100 mL)and water (50 mL). The organic layer was separated, washed with water(2×50 mL) and brine (25 mL), dried (MgSO₄) and evaporated under reducedpressure to give a yellow oil, which was purified by columnchromatography (EtOAc: isohexane 1:1) to give the title compound as a10:1 mixture of Z/E isomers (1.57 g, 92%).

¹H NMR 1.3 (s, 9H); 1.4 (s, 0.9H); 3.55 (s, 0.3H); 3.8 (s, 3H); 6.6 (s,0.1H); 7.2 (s, 1H); 7.25(d, 0.1H); 7.5 (d, 1H); 8.75 (d, 0.1H); 8.8 (s,1.1H); 8.85 (d, 1H); 9.2 (s, 0.11H); 9.25 (s, 1H); MS m/z 322.

Method 31

3-Nitroisonicotinaldehyde

4-Methyl-nitropyridine (1.43 g, 10.36 mmol) was dissolved in dry DME (5mL) and dimethylformamide dimethyl acetal (2.0 g, 16.8 mmol) was added.The mixture was heated under nitrogen at 140° C. for 2 hours and thenevaporated under reduced pressure to give(E)-N,N-dimethyl-2-(3-nitropyridin-4-yl)ethyleneamine as a dark redsolid. This was added in one portion at ambient temperature to a stirredsolution of sodium periodate (6.61 g, 31 mmol) in THF/Water 1:1 (100mL). After stirring for 2 hr at ambient temperature the reaction mixturewas filtered and the solid washed with ethyl acetate (100 mL). Thewashings were combined with the filtrate and organic layer separated.The aqueous was extracted with ethyl acetate (2×100 mL) and the combinedorganic layers were washed with saturated aqueous sodium bicarbonate(100 mL) and brine (100 mL), dried (MgSO₄) and evaporated under reducedpressure to give a brown solid which was purified by columnchromatography (DCM) to give the title compound. (960 mg, 61%).

¹HNMR 7.8 (d, 1H); 9.15 (d, 1H); 9.4(s, 1H); 10.4 (s, 1H)

1. A compound of formula (1):

wherein

is a single or double bond; X is N or CH; R⁴ and R⁵ together are—S—C(R⁶)═C(R⁷)— or —C(R⁷)═C(R⁶)—S—; R⁶ and R⁷ are independently selectedfrom hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl,difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, and C₁₋₄alkanoyl; A isphenylene or heteroarylene; n is 0, 1, or 2; R¹ is independentlyselected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl,N—C₁₋₄alkylcarbamoyl, N,N—(C-₁₋₄alkyl)₂carbamoyl, sulphamoyl,N—C₁₋₄alkylsulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, —S(O)_(b)C₁₋₄alkyl(wherein b is 0, 1, or 2), C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, hydroxyC₁₋₄alkyl,fluoromethyl, difluoromethyl, trifluoromethyl, and trifluoromethoxy; orwhen n is 2, the two R¹ groups, together with the carbon atoms of A towhich they are attached, may form a 4- to 7-membered ring, optionallycontaining 1 or 2 heteroatoms independently selected from O, S, and N,and optionally being substituted with one or two methyl groups; R² ishydrogen, hydroxy, or carboxy; R³ is selected from hydrogen, hydroxy,C₁₋₄alkoxy, C₁₋₄alkanoyl, carbamoyl, C₃₋₇cycloalkyl (optionallysubstituted with 1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl, aryl,heterocyclyl, C₁₋₄alkyl (optionally substituted with 1 or 2 R⁸ groups),and groups of the formulae B or B′

wherein y is 0 or 1, t is 0, 1, 2, or 3 and u is 1 or 2; provided thatthe hydroxy group is not a substituent on the ring carbon adjacent tothe ring oxygen; R⁸ is independently selected from hydroxy,C₁₋₄alkoxyC₁₋₄alkoxy, hydroxyC₁₋₄alkoxy, 5- and 6-membered cyclicacetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl,C₃₋₇cycloalkyl, C₁₋₄alkanoyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b)— (wherein bis 0, 1, or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1, or 2),arylS(O)_(b)— (wherein b is 0, 1, or 2), heterocyclylS(O)_(b)— (whereinb is 0, 1, or 2), benzylS(O)_(b)— (wherein b is 0, 1, or 2), —N(OH)CHO,—C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂,—C(═N—OH)NHC₃₋₆cycloalkyl, —C(═N—OH)N(C₃₋₆cycloalkyl)₂, —COCOOR⁹,—C(O)N(R⁹)(R¹⁰), —NHC(O)R⁹, —C(O)NHSO₂(C₁₋₄alkyl), —NHSO₂R⁹,(R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹, (R⁹)(R¹⁰)N—, and —COOR⁹; R⁹ and R¹⁰ areindependently selected from hydrogen, hydroxy, C₁₋₄alkyl (optionallysubstituted with 1 or 2 R¹³), C₃₋₇cycloalkyl (optionally substitutedwith 1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl, trihalo(C₁₋₄)alkyl, aryl,heterocyclyl, and heterocyclyl(C₁₋₄alkyl); or R⁹ and R¹⁰ together withthe nitrogen to which they are attached form a 4- to 6-membered ringwhere the ring is optionally substituted on carbon with 1 or 2substituents independently selected from oxo, hydroxy, carboxy, halo,nitro, cyano, carbonyl, C₁₋₄alkoxy, and heterocyclyl; or the ring may beoptionally substituted on two adjacent carbons with —O—CH₂—O— to form acyclic acetal wherein one or both of the hydrogens of the —O—CH₂—O—group may be replaced by a methyl; R¹³ is selected from hydroxy, halo,trihalomethyl, and C₁₋₄alkoxy; and R¹¹ is independently selected fromhydrogen, C₁₋₄alkyl, and hydroxyC₁₋₄alkyl; or a pharmaceuticallyacceptable salt or prodrug thereof; with the proviso that the compoundof formula (1) is not: (i)2,3-dichloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]4H-thieno[3,2-b]pyrrole;(ii)2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;or (iii)2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.2. A compound of claim 1, wherein R³ is selected from hydrogen, hydroxy,C₁₋₄alkoxy, C₁₋₄alkanoyl, carbamoyl, C₃₋₇cycloalkyl (optionallysubstituted with 1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl, morpholino,morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl,imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl,isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl,thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl,4-oxopydridyl, 2-oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl,oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrahydrothiopyranyl,1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, andC₁₋₄alkyl (optionally substituted with 1 or 2 R⁸ groups); R⁹ and R¹⁰ areindependently selected from hydrogen, hydroxy, C₁₋₄alkyl (optionallysubstituted with 1 or 2 R¹³ groups), C₃₋₇cycloalkyl (optionallysubstituted with 1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl, trihaloC₁₋₄alkyl, aryl, heterocyclyl, and heterocyclyl(C₁₋₄alkyl); or R⁹ andR¹⁰ together with the nitrogen to which they are attached form a 4- to6-membered ring where the ring is optionally substituted on carbon with1 or 2 substituents selected from oxo, hydroxy, carboxy, halo, nitro,cyano, carbonyl, and C₁₋₄alkoxy, or the ring may be optionallysubstituted on two adjacent carbons with —O—CH₂—O— to form a cyclicacetal wherein one or both of the hydrogens of the —O—CH₂—O— group maybe replaced by a methyl; R⁸ is independently selected from hydroxy,C₁₋₄alkoxyC₁₋₄alkoxy, hydroxyC₁₋₄alkoxy, 5- and 6-membered cyclicacetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl,C₃₋₇cycloalkyl, C₁₋₄alkanoyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b)— (wherein bis 0, 1, or 2), C₃₋₆cycloalkylS(O)_(b)— (wherein b is 0, 1, or 2),arylS(O)_(b)— (wherein b is 0, 1, or 2), heterocyclylS(O)_(b)— (whereinb is 0, 1, or 2), benzylS(O)_(b)— (wherein b is 0, 1, or 2), —N(OH)CHO,—C(═N—OH)NH₂, —C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂,—C(═N—OH)NHC₃₋₆cycloalkyl, —C(═N—OH)N(C₃₋₆cycloalkyl)₂, —COCOOR⁹,—C(O)N(R⁹)(R¹⁰), —NHC(O)R⁹, —C(O)NHSO₂(C₁₋₄alkyl), —NHSO₂R⁹,(R⁹)(R¹⁰)NSO₂—, —COCH₂OR¹¹, (R⁹)(R¹⁰)N—, and —COOR⁹; R¹³ is selectedfrom hydroxy, halo, trifluoromethyl, and C₁₋₄alkoxy; and R¹¹ is selectedfrom hydrogen, C₁₋₄alkyl, and hydroxyC₁₋₄alkyl; or a pharmaceuticallyacceptable salt or in-vivo hydrolysable ester thereof; provided that thecompound of formula (1) is not (i)2,3-dichloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole;(ii)2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;or (iii)2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.3. A compound of claim 1, wherein R³ is selected from cyanoC₁₋₄alkyl andC₁₋₄alkyl (optionally substituted with 1 or 2 R⁸ groups); R⁸ isindependently selected from hydroxy, phenyl,2,2-dimethyl-1,3-dioxolan-4-yl, 2,2-dimethyl-1,3-dioxan-4-yl;2,2-dimethyl-1,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl,tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothienyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (whereinb is 0, 1, or 2), —C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me, —C(═N—OH)NH₂,—C(═N—OH)NHC₁₋₄alkyl, —C(═N—OH)N(C₁₋₄alkyl)₂, and —NHSO₂R⁹; and R⁹ andR¹⁰ are independently selected from hydrogen, hydroxy, and C₁₋₄alkyloptionally substituted with R¹³ (wherein R¹³ is C₁₋₄alkoxy or hydroxy);or R⁹ and R¹⁰ together with the nitrogen to which they are attached forma 4- to 6-membered ring where the ring may be optionally substituted oncarbon with 1 or 2 hydroxy groups or carboxy groups, or the ring may beoptionally substituted on two adjacent carbons with —O—CH₂—O— to form acyclic acetal wherein one or both of the hydrogens of the —O—CH₂—O—group may be replaced by a methyl. or a pharmaceutically acceptable saltor in-vivo hydrolysable ester thereof; provided that the compound offormula (1) is not:2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.4. A compound of claim 1, wherein R³ is selected from cyano, C₁₋₄alkyland C₁₋₄alkyl (optionally substituted with 1 or 2 R⁸ groups); R⁸ isindependently selected from hydroxy, 2,2-dimethyl-1,3-dioxolan-4-yl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(b)— (wherein b is 0, 1, or 2),—C(O)N(R⁹)(R¹⁰), —COOR⁹, —C(O)NHSO₂Me, and —C(═N—OH)NH₂; and R⁹ and R¹⁰are independently selected from hydrogen, hydroxy, and C₁₋₄alkyloptionally substituted with R¹³ (wherein R¹³ is C₁₋₄alkoxy or hydroxy);or R⁹ and R¹⁰ together with the nitrogen to which they are attached forma 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine,pyrrolidine, 3,4-dihydroxypyrrolidine, and the dimethylacetal of3,4-dihydroxypyrrolidine; or a pharmaceutically acceptable salt orin-vivo hydrolysable ester thereof; provided that the compound offormula (1) is not2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.5. A compound of claim 1, wherein R⁴ and R⁵ together are —S—C(R⁶)═C(R⁷)—or a pharmaceutically acceptable salt or in-vivo hydrolysable esterthereof.
 6. A compound of claim 1, wherein R⁴ and R⁵ together are—C(R⁷)═C(R⁶)—S—, or a pharmaceutically acceptable salt or in-vivohydrolysable ester thereof.
 7. A compound of claim 1, wherein X is CH,or a pharmaceutically acceptable salt or in-vivo hydrolysable esterthereof.
 8. A compound of claim 1, wherein X is N, or a pharmaceuticallyacceptable salt or in-vivo hydrolysable ester thereof.
 9. A compound ofclaim 1, wherein A is phenylene, or a pharmaceutically acceptable saltor in-vivo hydrolysable ester thereof.
 10. A compound of claim 1,wherein A is heteroarylene, or a pharmaceutically acceptable salt orin-vivo hydrolysable ester thereof.
 11. A compound of claim 1, wherein

is a single bond, or a pharmaceutically acceptable salt or in-vivohydrolysable ester thereof.
 12. A compound of claim 1, selected from2-chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(carbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(N,N-dimethylcarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(N-methylcarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(N-hydroxycarbamoylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[N-(2-hydroxyethyl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrol-5-ylcarboxamide;2-chloro-N-[1-(2,3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[(2,2-dimethyl-1,3-dioxolan-4(S)-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(2(S),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide2-chloro-N-[1-(2(R),3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3(R,S)-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[N-(1,3-dihydroxyprop-2-yl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[N-(2-Methoxyethyl)carbamoylmethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-(1-{2-[(3a,6a-cis)-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-(1-{2-[(cis)-3,4-Dihydroxypyrrolidin-1-yl]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2,3-dichloro-N-{1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;2,3-dichloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;2-chloro-N-(1-{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[2-(methoxy)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[2-oxo-1-(1H-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-(1-{2-[(methylsulphonyl)amino]-2-oxoethyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;N-{1-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{2-oxo-1-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl]-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;N-{1-[(5-amino-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[2-(methylthio)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[2-(methylsulfinyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2,3-dichloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide;2,3-dichloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;2,3-dichloro-N-{1-[(2R)-2,3-dihydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-4H-thieno[3,2-b]pyrrole-5-carboxamide;2-chloro-N-{1-[3-(dimethylamino)-2-hydroxypropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{2-oxo-1-[(2-oxo-1,3-dioxan-5-yl)methyl]-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-{1-[3-(methylamino)-3-oxopropyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[2-oxo-1-(2-oxobutyl)-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2-chloro-N-[1-(2-hydroxybutyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;2,3-dichloro-N-[(6S)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-6-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;2,3-dichloro-N-(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;2-chloro-N-(2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;N-(6-fluoro-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;andN-(6-methoxy-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;or a pharmaceutically acceptable salt or an in-vivo hydrolysable esterthereof.
 13. A pharmaceutical composition which comprises a compound ofclaim 1, or a pharmaceutically acceptable salt or in-vivo hydrolysableester thereof in association with a pharmaceutically acceptable diluentor carrier.
 14. A method for the treatment of type 2 diabetes, insulinresistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiacischaemia, or obesity in a warm-blooded animal, comprising administeringa compound of claim 1, or a pharmaceutically acceptable salt or in-vivohydrolysable ester thereof.
 15. A process for the preparation of claim1, which process comprises: reacting an acid of the formula (2)

or an activated derivative thereof; with an amine of formula (3)

and thereafter if necessary i) converting a compound of the formula (1)into another compound of the formula (1); ii) removing any protectinggroups; or iii) forming a pharmaceutically acceptable salt or in-vivohydrolysable ester.